The MRE11 complex: An important source of stress relief

Rein, Katrin; Stracker, Travis H.

doi:10.1016/j.yexcr.2014.10.010

Cited by 26 publications

(37 citation statements)

References 90 publications

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“…Therefore, MRE11 is involved in neither p53-dependent idling nor the mechanism causing recombination. Therefore, exonucleolytic attack by MRE11 may be ultimately triggered by a persistent replication block that cannot be resolved by HLTF/ZRANB3 (77).…”

Section: Discussionmentioning

confidence: 99%

DNA damage tolerance pathway involving DNA polymerase ι and the tumor suppressor p53 regulates DNA replication fork progression

Hampp

Kießling

Buechle

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

161

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DNA damage tolerance facilitates the progression of replication forks that have encountered obstacles on the template strands. It involves either translesion DNA synthesis initiated by proliferating cell nuclear antigen monoubiquitination or less well-characterized fork reversal and template switch mechanisms. Herein, we characterize a novel tolerance pathway requiring the tumor suppressor p53, the translesion polymerase ι (POLι), the ubiquitin ligase Rad5-related helicase-like transcription factor (HLTF), and the SWI/SNF catalytic subunit (SNF2) translocase zinc finger ran-binding domain containing 3 (ZRANB3). This novel p53 activity is lost in the exonucleasedeficient but transcriptionally active p53(H115N) mutant. Wild-type p53, but not p53(H115N), associates with POLι in vivo. Strikingly, the concerted action of p53 and POLι decelerates nascent DNA elongation and promotes HLTF/ZRANB3-dependent recombination during unperturbed DNA replication. Particularly after cross-linkerinduced replication stress, p53 and POLι also act together to promote meiotic recombination enzyme 11 (MRE11)-dependent accumulation of (phospho-)replication protein A (RPA)-coated ssDNA. These results implicate a direct role of p53 in the processing of replication forks encountering obstacles on the template strand. Our findings define an unprecedented function of p53 and POLι in the DNA damage response to endogenous or exogenous replication stress.T he tumor suppressor protein p53 has been called the guardianof-the-genome due to its ability to transactivate downstream targets transcriptionally, which prevents S-phase entrance before facilitating DNA repair or eliminating cells with severe DNA damage via apoptosis (1). Interestingly, p53 also encodes an intrinsic 3′-5′ exonuclease activity located within its central DNA-binding domain (2-4). The contribution of the exonuclease proficiency to p53's function has largely remained obscure. Exonucleases are involved in DNA replication, DNA repair, and recombination, increasing the fidelity or efficiency of these processes. The 3′-5′ exonuclease activity of DNA polymerases (POLs) catalyzes the correction of replication errors, thereby preventing genomic instability and cancer (5-7). The potential involvement of p53's exonuclease in DNA repair has been ascribed to transcription-independent functions in nucleotide excision repair and base excision repair, in homologous recombination (HR), and in mitochondrial processes (8-10).Regarding HR, in particular, reports indicate a dual role for p53. On the one hand, it has been reported that p53 down-regulates unscheduled and excessive HR in response to severe genotoxic stress, like formation of DNA double-strand breaks (DSBs) (8-10). This antirecombinogenic effect of p53 has been linked to the blockage of continued strand exchange by interactions with recombinase RAD51, RAD54, and nascent HR intermediates carrying specific mismatches (11, 12). On the other hand, p53 stimulates spontaneous HR during S-phase to overcome replication fork stalling and to pr...

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Section: Discussionmentioning

confidence: 99%

DNA damage tolerance pathway involving DNA polymerase ι and the tumor suppressor p53 regulates DNA replication fork progression

Hampp

Kießling

Buechle

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

161

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“…Although NBS1 lacks enzymatic activity it provides regulatory functions through protein-protein interactions. 3 MRN is an early DSBs sensor that binds to DSBs and promotes Ataxia telangiectasia mutated (ATM) kinase activation. 4,5 ATM phosphorylates histone H2AX at serine 139 (gH2AX).…”

Section: Introductionmentioning

confidence: 99%

DNA damage response during mouse oocyte maturation

Mayer

Baran

Sakakibara³

et al. 2016

Cell Cycle

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Because low levels of DNA double strand breaks (DSBs) appear not to activate the ATM-mediated prophase I checkpoint in full-grown oocytes, there may exist mechanisms to protect chromosome integrity during meiotic maturation. Using live imaging we demonstrate that low levels of DSBs induced by the radiomimetic drug Neocarzinostatin (NCS) increase the incidence of chromosome fragments and lagging chromosomes but do not lead to APC/C activation and anaphase onset delay. The number of DSBs, represented by gH2AX foci, significantly decreases between prophase I and metaphase II in both control and NCS-treated oocytes. Transient treatment with NCS increases >2-fold the number of DSBs in prophase I oocytes, but less than 30% of these oocytes enter anaphase with segregation errors. MRE11, but not ATM, is essential to detect DSBs in prophase I and is involved in H2AX phosphorylation during metaphase I. Inhibiting MRE11 by mirin during meiotic maturation results in anaphase bridges and also increases the number of gH2AX foci in metaphase II. Compromised DNA integrity in mirin-treated oocytes indicates a role for MRE11 in chromosome integrity during meiotic maturation.

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“…NBS1 has a forkhead-associated domain and two BRCA1 C-terminal (BRCT) domains involved in phospho-dependent protein interactions in its N terminus and an MRE11 and PI3K-related protein kinase (PIKK) binding domain in its C terminus. 6,7 The latter domain interacts with ATM and is required for an efficient apoptotic response in the immune system. 7,8 Mutations in any MRE11 complex members or ATM underlies rare genetic instability syndromes with overlapping pathologies that affect the central nervous system, germline, and immune system.…”

Section: Introductionmentioning

confidence: 99%

NBS1 is required for macrophage homeostasis and functional activity in mice

Pereira-Lopes

Tur

Calatayud-Subias

et al. 2015

Blood

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• Nbs1 is a component of the MRE11 complex, which is a sensor of DNA double-strand breaks and plays a crucial role in the DNA damage response.• In mice with a hypomorphic allele of Nbs1, macrophages exhibit increased senescence and abnormal proliferation and inflammatory responses. , macrophage activation-induced ROS caused increased levels of DNA damage that were associated with defects in proliferation, delayed differentiation, and increased senescence. Furthermore, upon stimulation, Nbs1 ΔB/ΔB macrophages exhibited increased expression of proinflammatory cytokines. In the in vivo 2,4-dinitrofluorobenezene model of inflammation, Nbs1 ΔB/ΔB animals showed increased weight and ear thickness. By using the sterile inflammation by zymosan injection, we found that macrophage proliferation was drastically decreased in the peritoneal cavity of Nbs1 ΔB/ΔB mice. Our findings show that NBS1 is crucial for macrophage function during normal aging. These results have implications for understanding the immune defects observed in patients with NBS and related disorders. (Blood. 2015;126(22):2502-2510

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The MRE11 complex: An important source of stress relief

Cited by 26 publications

References 90 publications

DNA damage tolerance pathway involving DNA polymerase ι and the tumor suppressor p53 regulates DNA replication fork progression

DNA damage tolerance pathway involving DNA polymerase ι and the tumor suppressor p53 regulates DNA replication fork progression

DNA damage response during mouse oocyte maturation

NBS1 is required for macrophage homeostasis and functional activity in mice

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