SAMHD1 Promotes DNA End Resection to Facilitate DNA Repair by Homologous Recombination.
نویسندگان
چکیده
DNA double-strand break (DSB) repair by homologous recombination (HR) is initiated by CtIP/MRN-mediated DNA end resection to maintain genome integrity. SAMHD1 is a dNTP triphosphohydrolase, which restricts HIV-1 infection, and mutations are associated with Aicardi-Goutières syndrome and cancer. We show that SAMHD1 has a dNTPase-independent function in promoting DNA end resection to facilitate DSB repair by HR. SAMHD1 deficiency or Vpx-mediated degradation causes hypersensitivity to DSB-inducing agents, and SAMHD1 is recruited to DSBs. SAMHD1 complexes with CtIP via a conserved C-terminal domain and recruits CtIP to DSBs to facilitate end resection and HR. Significantly, a cancer-associated mutant with impaired CtIP interaction, but not dNTPase-inactive SAMHD1, fails to rescue the end resection impairment of SAMHD1 depletion. Our findings define a dNTPase-independent function for SAMHD1 in HR-mediated DSB repair by facilitating CtIP accrual to promote DNA end resection, providing insight into how SAMHD1 promotes genome integrity.
منابع مشابه
The Role of Long Non Coding RNAs in the Repair of DNA Double Strand Breaks
DNA double strand breaks (DSBs) are abrasions caused in both strands of the DNA duplex following exposure to both exogenous and endogenous conditions. Such abrasions have deleterious effect in cells leading to genome rearrangements and cell death. A number of repair systems including homologous recombination (HR) and non-homologous end-joining (NHEJ) have been evolved to minimize the fatal effe...
متن کاملRECQL4 Promotes DNA End Resection in Repair of DNA Double-Strand Breaks.
The RecQ helicase RECQL4, mutated in Rothmund-Thomson syndrome, regulates genome stability, aging, and cancer. Here, we identify a crucial role for RECQL4 in DNA end resection, which is the initial and an essential step of homologous recombination (HR)-dependent DNA double-strand break repair (DSBR). Depletion of RECQL4 severely reduces HR-mediated repair and 5' end resection in vivo. RECQL4 ph...
متن کاملThe Human SRCAP Chromatin Remodeling Complex Promotes DNA-End Resection
BACKGROUND Repair of DNA double-strand breaks (DSBs) by homologous recombination requires 5'-3' resection of the DSB ends. In vertebrates, DSB resection is initiated by the collaborative action of CtIP and the MRE11-RAD50-NBS1 (MRN) complex. However, how this process occurs within the context of chromatin is still not well understood. RESULTS Here we identify the human SRCAP chromatin remodel...
متن کاملTOPBP1Dpb11 plays a conserved role in homologous recombination DNA repair through the coordinated recruitment of 53BP1Rad9
Genome maintenance and cancer suppression require homologous recombination (HR) DNA repair. In yeast and mammals, the scaffold protein TOPBP1Dpb11 has been implicated in HR, although its precise function and mechanism of action remain elusive. In this study, we show that yeast Dpb11 plays an antagonistic role in recombination control through regulated protein interactions. Dpb11 mediates opposi...
متن کاملAnd-1 coordinates with CtIP for efficient homologous recombination and DNA damage checkpoint maintenance
To prevent genomic instability, cells respond to DNA lesions by blocking cell cycle progression and initiating DNA repair. Homologous recombination repair of DNA breaks requires CtIP-dependent resection of the DNA ends, which is thought to play a key role in activation of CHK1 kinase to induce the cell cycle checkpoint. But the mechanism is still not fully understood. Here, we establish that An...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- Cell reports
دوره 20 8 شماره
صفحات -
تاریخ انتشار 2017