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Abstract
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.
Highlights
The profound effects of c-Myc on cell growth, proliferation, apoptosis, and tumorigenesis have been mainly attributed to its ability to coordinate gene transcription. c-Myc is a basic helix-loop helix transcription factor that directly modulates transcription of a large number of genes controlled by all three RNA polymerases [2,3,4]. c-Myc can indirectly regulate transcription through up-regulation of histone acetylases, with the potential to globally influence chromatin structure [5]
PLoS ONE | www.plosone.org c-Myc and Werner DNA helicase protein (WRN) Role in S-Phase tolerate c-Myc overexpression using a retroviral vector, and exhibit c-Myc-specific phenotypes, but do not develop the senescence response that is seen in other cell types [21]
To examine the duration of S-phase, human foreskin fibroblasts (HFF)-pB and HFF-Myc cells were synchronized at the G1/S boundary by double thymidine block
Summary
The profound effects of c-Myc on cell growth, proliferation, apoptosis, and tumorigenesis have been mainly attributed to its ability to coordinate gene transcription. c-Myc is a basic helix-loop helix transcription factor that directly modulates transcription of a large number of genes controlled by all three RNA polymerases [2,3,4]. c-Myc can indirectly regulate transcription through up-regulation of histone acetylases, with the potential to globally influence chromatin structure [5]. The co-localization of BrdU and cH2AX was compared in hTERT- WRN+/+ -fibroblasts versus hTERT-WRN2/2 fibroblasts after c-Myc overexpression with the c-Myc retroviral vector, LXSN-Myc. c-Myc expression in hTERT-WRN2/2 cells led to a 3.5-fold increase in c-H2AX foci co-localizing with BrdU, relative to hTERT-WRN2/2 cells with empty vector (Fig. 3a and 3b), indicating c-Myc induced DNA damage occurs at sites of DNA replication.
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