越来越庞大的衰老抗衰老研究中国军团——2016杭州衰老及老年病大会“生煎包”

杭州的G20刚刚落下帷幕，2016.9.9，乱花迷人的西湖边，衰老抗衰老研究中国军团就在杭州师范大学的主持下开了个很“洋气”的大会。为了让国内衰老研究同行跟上衰老研究新时代混乱的步伐，这里把会议消息介绍如下，不懂“鹰文”的民科就请将就着猜两下。看不懂没有关系，科学前沿，特别是像衰老这样的“科学航空母舰”巨问题，世界上是没有几个大侠真的能雾里看出花来的。

下面先给出节选，想一口吃撑成胖子，或是想看看作报告的大侠的尊容的可看博文后面的附件：

衰老研究所,  杭州师范大学

E-News ——2016年7-8月期

2016 InternationalConference on Aging Research:

Molecular Mechanismsand Associated Diseases

Hangzhou, Zhejiang,China

September 9-11, 2016

Table of Contents

Conference Committees.................................................................................................1

Program..........................................................................................................................2

Plenary I Healthy aging andmetabolism .......................................................................6

Guang Ning...............................................................................错误!未定义书签。

Session 1: Mechanisms regulatingaging..................................................................... 7

Jing-Dong Jackie Han...............................................................................................7

Zhongjun Zhou..........................................................................................................8

Session 2: Stress signaling andmetabolic aging ....................................................... 10

Nick Musi................................................................................................................10

Feng Liu..................................................................................................................11

Yuying Zhang, Kaiyuan Wu, WentingSu, Chang Chen ......................................... 12

Session 3: Inflammation in agingand related disorders ............................................ 14

Bryan R. G.Williams, Afsar U.Ahmed ................................................................... 14

Matthew J Sweet.....................................................................................................15

Hui Y. Lan...............................................................................................................16

Session 4: Neural degenerativedisease in aging ....................................................... 19

Zhuohua Zhang.......................................................................................................19

Biao Chen................................................................................................................20

Jun-Ping Liu............................................................................................................21

Yanjiang Wang........................................................................................................22

Xiaotao Li ................................................................................................................23

Plenary II Telomere and agingdiseases....................................................................... 25

Jerry W. Shay ..........................................................................................................26

Session 5: Telomere and genomeinstability in aging (1) .......................................... 27

Peili Gu, Yang Wang, SusanBailey, et al. ...............................................................27

Ming Lei....................................................................................错误!未定义书签。

Laetitia Maestroni, StéphaneCoulon, Vincent Géli ................................................ 29

Zhou Songyang.......................................................................................................30

Ning Liu, Deqiang Ding andYu-Sheng Cong ......................................................... 31

Session 6: Mitochondrialdysfunction in aging .........................................................32

Michael V Berridge.................................................................................................32

Quan Chen...............................................................................................................34

Justin St. John..........................................................................................................35

Session 7: Tissue stem cell aging..............................................................................37

Peter Lansdorp........................................................................................................37

Zhenyu Ju................................................................................................................38

Lin Liu, Jiao Yang...................................................................................................39

Guang-Hui Liu........................................................................................................41

Session 8: Cardiovascular andother aging-related diseases ..................................... 43

QiulunLu, YufengYao, QingKennethWang ............................................................ 43

Michal Berndt..........................................................................................................45

Jian Li........................................................................................错误!未定义书签。

Xiangmei Chen........................................................................................................46

Plenary III Epigenetic regulationof longevity............................................................. 47

Vera Gorbunova ......................................................................................................48

Session 9: Longevity andmechanisms...................................................................... 49

Xiao-Li Tian............................................................................................................49

Yousin Suh..............................................................................................................51

Xiao-Ling Li, Ze Yang............................................................................................52

Ejun Huang..............................................................................................................53

Session 10: Telomere and genomeinstability in aging (2) ........................................ 54

Jing Peng, Qiong-Di Zhang,Jin-Qiu Zhou ............................................................. 54

Eric Gilson..............................................................................................................56

Jun Xing, Yiling Ying, Wai IanLeong, et al ........................................................... 57

Yong Zhao...............................................................................................................59

Session 11: Signaling defect inaging ........................................................................60

John Speakman........................................................................................................60

Yang Wang, Zhi-Xiong Jim Xiao............................................................................ 61

Jianfeng Liu.............................................................................................................62

Baohua Liu..............................................................................................................63

Session 12: Mechanisms of ovarianaging ................................................................ 64

Hui Chen, YechunRuan, XiaohuaJiang, Hsiao Chang Chan .................................. 64

Chao Yu, Yin-Li Zhang, Heng-YuFan .................................................................... 66

Plenary IV Signaling networks intissue stem cell aging ............................................. 68

Xinhua Feng............................................................................................................69

Poster Presentations.....................................................................................................70

I. Brain degenerative diseases...................................................................................71

Fei Dou....................................................................................................................71

Jian Fu, Zi Zhou, Ya Fang.......................................................................................72

Feijuan Huang, Xianxiang Tian,Guangshan Xie, et al. .......................................... 73

Wang-Sheng Jin, Yan-JiangWang...........................................................................75

Zhigang Liu, Yuwei Chen, QianLiu, et al .............................................................. 76

Lin-Lin Shen,

Yan-Jiang Wang ...............................................................................77

Fei Wang, Guangming Chang, XinGeng................................................................ 78

Ping Wang, Zi Zhou, Ya Fang.................................................................................79

II. Cardiovascular diseases........................................................................................80

Shi-lian Hu, Xiang Fang, Shi Yin,Gan Shen .......................................................... 80

III. Cancer biology.....................................................................................................82

Yu-Sheng Guo, Hong-Guo Jiang,Shu-Ting Jia, Ying Luo ..................................... 82

Dongsheng Shang, Yanfang Wu,Zhigang Tu ......................................................... 84

Hang Yu, Xiaosun Liu, YanyunHong, et al ............................................................ 85

IV. Digestion, metabolism andendocrine diseases .................................................... 86

Yu-ning Chen, Meng-yun Cai, ShunXu, et al ........................................................ 86

Fangyuan Dong, Yan Zhang, YiqinHuang, et al ..................................................... 87

Fengyi Gao, Guoping Li, Chao Liu,et al ................................................................ 88

Weiquan Li..............................................................................................................89

Zhen Li....................................................................................................................90

Zhongchi Li,Kang Xu, Sen Zhao, etal ................................................................... 91

Fuzhi Lian, Jinquan Wang, YuchaoLiu, et al .......................................................... 92

Yang Liu, Zhang Rui, Alex.....................................................................................94

Zhigang Liu, Qinglian Qiao, YaliSun, et al ............................................................ 95

Guoliang Lv, Yiting Guan, Wei Tao........................................................................ 96

Chi-Hao Shao, Kun Wu, Hai-Li Li,et al ................................................................. 98

Xue-qing Zhang, Yi Yu, Fang Pang,et al ................................................................ 99

Ru-Yi Zhang, Kang Gao, Dan Zhao,et al ............................................................. 100

Yin-Li Zhang, Jue Zhang, Long-WenZhao, Heng-Yu Fan ................................... 101

Zepeng Zhang, Tianpeng Zhang,Haiying Liu, et al ............................................. 102

Mushi Chen...........................................................................................................103

V. Virus infection and immunerelated diseases ...................................................... 104

Yang Xiang, Yuyan Zhang, YunZhang ................................................................. 104

VI. Cell therapy and stem cellbiology ....................................................................106

Hong-Jing Cui, Xin-Gang Cui, WeiZhao, et al .................................................... 106

Zhi-Wen Jiang, Hui-Ling Zheng,Wei-Chun Chen, et al ....................................... 107

Jianfeng Liu...........................................................................................................108

Shun Xu, Hai-Jiao Huang, BingZhang, et al ........................................................ 109

Wei Zhao, Hua-zhen Zheng, TaoZhou, et al ........................................................ 110

VII. Traditional Chinesemedicine, drug development and clinical trials ............... 111

Lei Peng, Jing Liu, Wen-HuiHuang, et al ............................................................ 111

Ling Xiao..............................................................................................................113

Cheng-Kui Xiu, Yan Lei.......................................................................................114

Jing Yang, Yan Lei.................................................................................................115

List of Participants.....................................................................................................116

Plenary I

Healthy aging and metabolism

Session 1: Mechanisms regulatingaging

A systems approach to reverseengineer lifespan extension by dietary restriction

Jing-Dong Jackie Han

Dietary restriction (DR) is themost powerful natural means to extend lifespan. Although

several  genes can  mediate  responses to  alternate  DR regimens,  no  single genetic intervention has recapitulated the full effects of DR, and nounified system is known for

different  DR regimens.  Here  we obtain  temporally  resolved transcriptomes  during chronic  DR and  intermittent  fasting (IF)  in  Caenorhabditis  elegans, and  find  that early and  late  responses involve  metabolisms,  and cell  cycle/DNA  damage, respectively.  We uncover  three network  modules  of regulators  by  target specificity.  By  genetic manipulations  of nodes  representing  discrete modules,  we  induce transcriptomes  that progressively  resemble DR  as  multiple nodes  are  perturbed. Targeting  all  three nodes simultaneously  results  in extremely  long-lived  animals that  that  are refractory  to  DR. These results  and  dynamic simulations  demonstrate  that extensive  feedback  controls among regulators may be leveraged todrive the regulatory circuitry to a younger steady state, recapitulating thefull effect of DR.

Genetics and epigenetics: fromaccelerated aging to human aging

Zhongjun Zhou    

Faculty of Medicine, TheUniversity of Hong Kong

Abnormal splicing of LMNA genegives rise to a truncated prelamin A termed as progerin which is accumulated inpatients suffering from Hutchinson-Gilford progeria Syndrome. Lamin  A interacts  with  and activates  a  variety of  nuclear  factors including  histone modifying  enzymes such  as  MOF, SUV39H1,  SIRT1  and SIRT6.  The  presence of progerin  compromises  the proper  association  of these  important  nuclear proteins  with nuclear matrix,leading to defective chromatin remodeling in response to DNA damage. The  nuclear lamin  A  also serves  as  activators for  SIRT1  and SIRT6  that  are critical  in stem  cell maintenance  and  DNA damage  repair.  Targeting the  epigenetic  changes significantly  rescue the  cellular  senescence and  extend  lifespan in  progeroid  mice.Our studies suggest a profound role forlamin A in regulating nuclear architecture, chromatin dynamics and stem cellpotency that all contribute to the aging processes  Acknowledgements These works are supported bygrants from Research Grant Council (CRF/GRF) of Hong Kong and Natural ScienceFoundation of China.

Session 2: Stress signaling andmetabolic aging

Pros and cons of suppressinginflammation in aging

Nick Musi

Adipose mTORC1 signaling andfunction in metabolic homeostasis

Feng Liu

Metabolic Syndrome ResearchCenter, the Second Xiangya Hospital, Central South University

Mammalian/Mechanistic  target of  rapamycin  (mTOR) is  a  key  energy  sensor and  its dysregulation  is associated  with  various aging-associated  diseases.  Studies have  shown that inhibition of themTOR signaling pathway extends lifespan in experimental animals. However,  chronic and  whole-body  suppression of  this  signaling pathway  may  lead to serious  side  effects, suggesting  that  tissue-specific  inhibition of  this  signaling pathway may promote healthy aging. Adipose  tissue synthesizes  and  secretes numerous  hormones  or cytokines  (adipokines) that  play a  major  role in  the  maintenance of  energy  homeostasis in  our  body.  In  this presentation,  I will  briefly  summarize our  recent  studies on  the  roles of  adipose  tissue mTOR complex  I  (mTORC1) signaling  in  regulating beige  fat  development and  energy homeostasis.  Comprehensive analysis  of  key signaling  pathways  involved in  the regulation of adipocytebiology  and function should shed newlight on the development of novel therapeutic treatments for variousaging-associated diseases.

Say NO to aging: the key enzymeof S-nitrosation GSNOR in age related cognitive impairment

Yuying Zhang, Kaiyuan Wu, WentingSu, Chang Chen

National Laboratory of Biomacromolecules,Institute of Biophysics, Chinese Academy of Sciences, 15

Datun Road, Chaoyang District,Beijing 100101, China.

The  free radical  theory  of aging  proposed  by Harman  in  1956 had been paid  widely attention, whichsuggests that free radicals damage cellular macromolecules cause aging. However,more  and more  studies  show the  other  side of  free  radicals in  signaling  and physiological function. Here we foundthat S-nitrosoglutathione reductase (GSNOR), the key  enzyme metabolizing  the  intracellular nitric  oxide  (NO) and  S-nitrosation, significantly  increased in  the  hippocampus of  both  aging human and mice. Neuronal specific overexpression of GSNOR leads tocognitive impairment, long-term potentiation (LTP) defect and lower dendritespine density. While knock out GSNOR rescued the age related  cognitive impairment.  We  then performed  liquid  chromatography-tandem  mass spectrometry (LC-MS/MS)-basedquantitative proteomic analysis of protein S-nitrosation and foundS-nitrosation of CamKIIα was significantly decreased in the hippocampus of aging  mice and GSNOR  transgenic mice. In  consistant  with the  change  of CamKIIα S-nitrosation,  the accumulation  of CamKIIα  in  hippocampal synaptosomal  and  its downstream  signaling p-GLUR1  and CREB/c-fos  were  also significantly  decreased, which  can all  be  rescued in  GSNOR  knock out mice.  We  further verified that  the S-nitrosationof CamKIIα is responsible for the CamKIIα synaptosomal accumulation by CamKIIαS-nitrosated sites (C280/289) mutant experiment. The cognitive impairment in GSNORtransgenic mice can be rescued by up-regulation of the NO signaling pathway or CamKIIα/CREB  signaling pathway.  In  summary, our  research  demonstrated that GSNOR  impaired  cognitive function  in  aging through  de-nitrosation  of CamkIIα. GSNOR is a new potential target for treatment of the agerelated cognitive impairment. In contrast to the free radical theory of aging,NO signaling deficiency may be the main cause to  induce  age-related cognitive  impairment.  In addition,  we  explored the physiological function of S-nitrosation of CamKIIα for the firsttime.

Session 3: Inflammation in agingand related disorders

The role of Integrin-linkedkinase in aging, innate immunity and cancer Bryan R. G.Williams and Afsar U.Ahmed

Centre for Cancer Research,Hudson Institute of Medical Research, Clayton, Victoria 3164, Australia

Integrin-Linked Kinase (ILK) is aubiquitously expressed protein that forms an important component  of cell  matrix  adhesions to  regulate  integrin function  in  response to a  wide variety of extracellularstimuli. ILK dysregulation is a feature of different human diseases including  cancer and  cardiovascular  disease. Although  deletion  of ILK  is  embryonic lethal, reduced levels of ILK havebeen associated with extended lifespans in C. elegans and Drosophila.  Reduced ILK  levels  also lessen  the  effects of  normal  cardiac aging  in Drosophila.  In primary  cardiac  myocytes reduced  ILK  expression prevents  the phenotypic  changes associated  with  senescence seen  in  aging cells.  Conversely  an increase in  ILK expression can induce premature senescence. Overexpression of  ILK is also a  feature  of different  cancers.  Impaired innate  immune  responses are  a  feature of aging  but  whether ILK  is  implicated has  not  been determined.    However,  we have shown that there is a role for ILK in regulating the innate immunesystem. Pharmacologic or  genetic  inhibition of  ILK  in mouse embryo  fibroblasts  and macrophages  selectively blocks  LPS-induced production  of  the pro-inflammatory  cytokinesILK  is required  for TLR-induced  NF-B activation  and  transcriptional  induction of  TNF-,  through an ILK-PI3K  axis.  The modulation  of  LPS-induced TNF- synthesis  by  ILK does  not involve  the classical  NF-B  pathway since  IkB  degradation and  p65  nuclear translocation  are both  unaffected  by  ILK  inhibition. Instead,  ILK  is involved  in  a non-classical activation of NF-B signalingby modulating the phosphorylation of p65 at ser536.  Furthermore, ILK-mediated  non-classical NF-Bactivation  through  p65 ser536 phosphorylation  also  exists in  a  host-pathogen interaction in  Helicobacter  pyroli infection.  Thus ILK  as  a critical  regulatory  molecule for  NF-B-  mediated proinflammatory signaling pathwayand regulation of innate immune responses.

Innate immune pattern recognitionreceptors and pathological inflammatory responses

Matthew J Sweet

Institute for MolecularBioscience, University of Queensland, Brisbane, Qld, 4072, Australia

Aging populations areparticularly susceptible to a range of chronic inflammation-related diseases,  as well  as  infectious diseases.  Innate immune  cells such  as  macrophages are central  mediators  of host  defence  against invading  pathogens,  and also  coordinate inflammatory  responses. These  cells  detect and  respond  to  danger through  several families  of pattern  recognition  receptors, of  which  the Toll-like receptors  (TLRs)  and inflammasome-forming Nod-like Receptors(NLRs) are the most widely studied. Histone deacetylases  (HDACs), a  family  of enzymes  most  widely studied  in  the context  of epigenetic  control of  gene  expression, are  key  regulators of lifespan,  inflammation  and host defence. Inhibitors of these enzymeshave also been developed as anti-cancer drugs, but  applications in  other  disease areas  require  more detailed  knowledge  of the  role  of individual HDACs  in  inflammation and  host  defence. We have  been  studying specific molecular mechanisms  by  which individual  HDAC  enzymes regulate macrophage-mediated inflammation and anti-bacterial responses,including via control of TLR-inducible mitochondrial  reactive  oxygen species  production.  These studies  have revealed  specific HDAC  enzymes  as  new  candidate targets  for  anti-inflammatory  and anti-infective drug development.

TGF-beta signaling in tissuerepair: role of Smad3

Hui Y. Lan

Department of Medicine &Therapeutics, Li Ka Shing Institute of Health Sciences, and Shenzhen Research Institute,The Chinese University of Hong Kong, Hong Kong, China  

Increasing evidence shows thatTGF- plays a critical role in cell repair or tissue fibrosis in  both physiological  and  pathological conditions.  It  is now  well  accepted that TGF-βcauses  cell  cycle arrest  at  the G1  phase  and thereby  potently  inhibits cell proliferation. However, the signaling mechanism of TGF- thatregulates these processes remains unknown. In the kidney, tubular epithelial cells (TECs) play a determinant rolein the tissue repair or  fibrosis  in response  to acute injury and  the degree  of  TEC regeneration  or  repair largely  determines the  progression  or repair  of acute  kidney injury.  We  found that  in  a mouse model  of  ischemia-induced  acute kidney  injury,  deletion of  Smad3,  a  key downstream  mediator of  TGF-/Smad  signaling, can  protect  kidney from  the  acute kidney injury  by  largely suppressing  p27, thereby  promoting  CKD2/cyclin E-dependent TEC proliferation.  In  contract, enhanced  Smad3  signaling by  deleting  Smad7, an inhibitor of Smad signaling, results in more severe acute kidneyinjury by impairing TEC regeneration via  the  Smad3-p27-dependent  mechanism. We also  found  that activated Smad3 can bind directly to p27 to suppress CKD2/cyclinE-dependent TEC proliferation, which is inhibited  by  a Smad3  inhibitor,  identifying activation  of  the Smad3-p27 pathway as a key mechanism bywhich TGF-1 induces the cell growth arrest at the G1 phase. More importantly,we also find that deletion of Smad7 promotes Smad3-mediated tissue fibrosisafter acute renal injury, suggesting that Smad3 palys a dual  role intissue repair  and  fibrosis. In  conclusion,  TGF- may impair  the  tissue repair  and  cause renal fibrosis via the Smad3-dependent mechanism. Thus, targeting Smad3may represent as a novel  and  effective therapy  for  both acute  and  chronic kidney  diseases,  including aging-related kidney disorders.

Session 4: Neural degenerativedisease in aging Molecular dissection of Parkinson disease

Zhuohua Zhang

Aging, alpha-Synuclein andParkinson's disease

Biao Chen

Lysosomal homeostasis, motor andnon-motor behavioral defects in Parkinson’s disease

Jun-Ping Liu

Institute of Aging Research,Hangzhou Normal University, Hangzhou, Zhejiang Province, China

The lysosomes of various sizedintracellular organelles act as the waste disposal system by sequesteringunwanted materials transported from the cytoplasm and taken-up through endocytosis.With  >50  different enzyme  types  including >50  cysteine,  serine and aspartate  proteases  responsible for  more  than 30  different  human genetic  diseases, lysosomes  require optimal  homeostasis  of  pH,  lipidic composition  and  ionic specificity for functionality. The lysosomal storage diseases aremonogenic disorders resulting from an accumulation of specific substratesowning to the inability to dispose them. Occurring at a frequency of 1 in 5,000live births, the diseases are genetically susceptive to inherited defects  in genes  that  mainly encode  lysosomal  proteins and involved in  aging-related diseases  such as neurodegenerative disorders,  cancer,  cardiovascular  diseases

.

ATP13A2 (PARK9) is a lysosomalintegral membrane ATPase enriched in the brain and mutated  in early-onset  Parkinsonism and  dementia  in man.  To  investigate the  roles  of ATP13A2 in  the  etiology of  Parkinson  disease (PD),  we mapped  ATP13A2 gene expression and intracellular localization, inactivated the ATP13A2gene, and determined its  roles  in trans-lysosomal  membrane  transport. Furthermore,  we  investigated the cellular basis of ATP13A2 mutation in PD phenotypes. We found thatthe orbital frontal, basal ganglia and hypothalamic regional aging is involvedin the behavioral compulsivity associated with anxiety and motor deficit,recapitulating PD impulse control disorder in a novel lysosomal setting.  

References:

1 Platt,  F.  M. Sphingolipid  lysosomal  storage disorders. Nature 510, 68-75,  doi:10.1038/nature13476 (2014).

2 Platt, F. M., Boland, B. & van der Spoel, A. C. The cell biology ofdisease: lysosomal storage disorders: the cellular  impact  of lysosomal  dysfunction.  The Journal  of  cell biology  199,  723-734,

Peripheral therapeutic approachfor Alzheimer's disease

Yanjiang Wang

Potential role of the REGgammaproteasome in aging brain disorder

Xiaotao Li

Shanghai Key Laboratory ofRegulatory Biology, Institute of Biomedical Sciences, School of Life Sciences;

Key  Laboratory of  Brain  Functional Genomics,  Ministry  of  Education,East  China  Normal University,

Shanghai, 200062, China

REGγ, an important proteasomeactivator to promote ubiquitin–independent protein

degradation, has beendemonstrated to degrade numerous intact proteins and is involved

in the regulation of importantbiological and pathological processes. We have previously

shown that REGγ deficiencyresults in premature aging. Here we demonstrate that REGγ

knockout (REGγ -/-) mice exhibitbrain disorders, including decreased working

memories, defective prepulseinhibition (PPI), and disability in nest building, at the age

of 8 months, reminiscent of brainaging. Mechanistically, REGγ promoted the

degradation of GSK3β protein, akinase involved in phosphorylation of tau. Consistently,

REGγ-depletion significantlyaugmented phosphorylated tau. Inhibition of GSK3β

rescued the compromised PPIphenotypes in the REGγ -/- mice. Also, we found an

age-dependent decrease in thetrypsin-like proteasomal activity in REGγ -/- mice brains.

Our data provide new indicationsthat REGγ-proteasome dysfunction may be involved in

brain degenerative diseases.

Plenary II

Telomere and aging diseases

Role of telomeres and telomerasein aging and cancer

Jerry W. Shay

Department of Cell Biology,University of Texas Southwestern Medical Center, Dallas, TX USA

Human  telomeres progressively  shorten  throughout life.  A  hallmark of  advanced

malignancies is the ability forcontinuous cell divisions that almost universally correlates

with the stabilization oftelomere length by the reactivation of telomerase. The repression

of  telomerase and  shorter  telomeres in  humans  may have  evolved  in part  as  an anti-cancer protection mechanism. Whilethere is still much we do not understand about the  regulation of  telomerase,  it remains a  very  attractive and  novel  target for  cancer therapeutics.  This presentation  will  focus on  the  current state  of  advances in  the telomerase  area, identifies  outstanding  questions, and  addresses  areas and  methods  that need refinement.

Session 5: Telomere and genomeinstability in aging (1)

mPOT1a and mPOT1b play distinctroles in telomere end protection

Peili Gu

Aging  is associated  with  progressive telomere  shortening,  resulting in  the  formation of dysfunctional  telomeres  that compromise  tissue  proliferation.  However, dysfunctional telomeres  also  limit tumorigenesis  by  activating p53-dependent  cellular  senescence and apoptosis.  Protection  of Telomere  1  (POT1) is  an  essential component  of  the shelterin complex and functions to maintain chromosome stability byrepressing the activation of aberrant DNA damage and repair responses attelomeres. Humans have one hPOT1 gene, while mice  possess  two POT1  proteins,  mPOT1a  and mPOT1b.  Sporadic  and familial mutations  in  the oligosaccharide-oligonucleotide (OB)  folds  of hPOT1  have  been identified in many cancers, but themechanism underlying how hPOT1 mutations initiate tumorigenesis  has remained  unclear.  Here we  show  that the  hPOT1‟s OB-folds  are essential  for the  protection  of newly  replicated  telomeres. Oncogenic  mutations  in hPOT1 OB-fold  fail  to bind  to  ss telomeric  DNA,  eliciting a  DNA  damage response  at telomeres thatpromote inappropriate  chromosome fusionsvia the mutagenic alternative non-homologous end  joining  (A-NHEJ) pathway.  hPOT1  mutations also  result  in telomere elongation  and  the formation  of  transplantable  hematopoietic malignancies.  

Strikingly, conditional deletionof both mPot1a and p53 in mouse mammary epithelium resulted in development ofhighly invasive breast carcinomas and the formation of whole chromosomescontaining massive arrays of telomeric fusions. In contrast, we found that -Chk1  dependent DNA  damage  response to  initiate  a robust  p53-independent, p73-dependent  apoptotic pathway  that  limited stem  cell  proliferation but  suppressed B-cell  lymphomagenesis.  Our results  demonstrate  that mPOT1a  and  mPOT1b play distinct roles in telomere end protection.    

Rearrangement of eroded telomeresin quiescent fission yeast cells

Laetitia Maestroni, StéphaneCoulon, and Vincent Géli

Cancer Research Centre ofMarseille, 27 boulevard Lei Roure, 13273, Marseille, France

Telomere length is highlyvariable between tissues and organs and inversely related to chronological  age. While  the  mechanisms of  telomere  maintenance have  been investigated individing cells, little is known about the stability of telomeres in quiescent cellsand how dysfunctional telomeres are processed in non-proliferating cells. Totackle this  issue  we examined  the  stability of  telomeres  in  quiescent  cells using  fission  yeast cells that  can  be maintained  for  weeks in  quiescence  by nitrogen  starvation.  We have investigated  how  eroded telomeres  are  processed during  quiescence  and the  fate  of quiescent cells  harboring  these short  telomeres.  By deleting  the  RNA component  of telomerase, we havefirst monitored the progressive telomere shortening after successive divisions.  Then cells  with  short telomeres  were  placed under  conditions  in which  they enter  into quiescence.  While  WT telomeres  are  stable in  quiescence,  strikingly we observed  that  short telomeres  were highly  rearranged.  We have  determined  that these rearrangements depended  on  homologous recombination  and  corresponded to  the expansion  of subtelomeric  regions  (named STEEx).  We have  identified a homologous sequenceof 226 bp within subtelomeric regions that might be used as a seed to promote recombination.We have further monitored the impact of STEEx on cell mortality during quiescenceand at the exit of quiescence. We first observed that the mortality of cells inthe  absence  of telomerase  is  correlated with  the  shortening of  telomeres  and the  time spent in quiescence.Second, STEEx were not maintained when cells exit quiescence to re-enter into  the  cell cycle.  We  thus describe  in  fission yeast  a new  mode of  telomere maintenance in theabsence of telomerase that is promoted in quiescence. This discovery highlightshow non-dividing cells that harbor eroded telomeres may circumvent the lack ofa functional telomere protection in the absence of replication.  

Mechanisms of telomere protectionin human cells

Zhou Songyang ………

E-News 2016年7-8月期.pdf