c-Myc accelerates S-phase and requires WRN to avoid replication stress.
c-Myc interacts with components of the pre-replication complex and directly regulates DNA replication [1]. However the consequences of this novel c-Myc function on cell cycle dynamics and replication-associated damage are unknown. Here, we show that c-Myc overexpression in primary human fibroblasts markedly accelerates S-phase while c-Myc deficient fibroblasts exhibit a prolonged S-phase. We also show that the Werner DNA helicase protein (WRN) plays a critical role in supporting c-Myc-driven S-phase, as depletion of WRN in c-Myc overexpressing cells increases DNA damage specifically at sites of DNA synthesis. This excess DNA damage activates a "replication stress" pathway involving ATR, CHK1, CHK2, and p53, leading to rapid senescence of WRN deficient c-Myc overexpressing cells. Indeed, depletion of p53 rescues this senescence response. We propose that WRN functions to repair abnormal replication structures caused by the acceleration of DNA replication by c-Myc. This work provides an additional mechanistic explanation for c-Myc-induced DNA damage and senescence, and reveals a vulnerability of c-Myc overexpressing cells that could potentially be exploited in cancer therapy.
Robinson
Kristin
K
Program in Cancer Biology and Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
Asawachaicharn
Nichaya
N
Galloway
Denise A
DA
Grandori
Carla
C
D000818:Animals; D002460:Cell Line; D016922:Cellular Senescence; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication; D005090:Exodeoxyribonucleases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D016271:Proto-Oncogene Proteins c-myc / Q000172:deficiency / Q000378:metabolism*; D034622:RNA Interference; D051381:Rats; D053484:RecQ Helicases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016196:S Phase; D000071657:Werner Syndrome Helicase
D016271:Proto-Oncogene Proteins c-myc; D005090:Exodeoxyribonucleases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase