Snm1B/Apollo Mediates Replication Fork Collapse and S Phase Checkpoint Activation in Response to DNA Interstrand Cross-links

Overview

Journal Oncogene

Specialties Molecular Biology
Oncology

Date 2008 May 13

PMID 18469862

Citations 40

Authors

J-B Bae

S S Mukhopadhyay

L Liu

N Zhang

J Tan

S Akhter

X Liu

X Shen

L Li

R J Legerski

Affiliations

Soon will be listed here.

Abstract

The removal of DNA interstrand cross-links (ICLs) has proven to be notoriously complicated due to the involvement of multiple pathways of DNA repair, which include the Fanconi anemia/BRCA pathway, homologous recombination and components of the nucleotide excision and mismatch repair pathways. Members of the SNM1 gene family have also been shown to have a role in mediating cellular resistance to ICLs, although their precise function has remained elusive. Here, we show that knockdown of Snm1B/Apollo in human cells results in hypersensitivity to mitomycin C (MMC), but not to IR. We also show that Snm1B-deficient cells exhibit a defective S phase checkpoint in response to MMC, but not to IR, and this finding may account for the specific sensitivity to the cross-linking drug. Interestingly, although previous studies have largely implicated ATR as the major kinase activated in response to ICLs, we show that it is activation of the ATM-mediated checkpoint that is defective in Snm1B-deficient cells. The requirement for Snm1B in ATM checkpoint activation specifically after ICL damage is correlated with its role in promoting double-strand break formation, and thus replication fork collapse. Consistent with this result Snm1B was found to interact directly with Mus81-Eme1, an endonuclease previously implicated in fork collapse. In addition, we also show that Snm1B interacts with the Mre11-Rad50-Nbs1 (MRN) complex and with FancD2 further substantiating its role as a checkpoint/DNA repair protein.

Citing Articles

Structure and Function of SNM1 Family Nucleases.

Wu H, Zheng Y, Laciak A, Huang N, Koszelak-Rosenblum M, Flint A Adv Exp Med Biol. 2022; 1414:1-26.

PMID: 35708844 DOI: 10.1007/5584_2022_724.

Dual targeting of Saccharomyces cerevisiae Pso2 to mitochondria and the nucleus, and its functional relevance in the repair of DNA interstrand crosslinks.

Somashekara S, Muniyappa K G3 (Bethesda). 2022; 12(6).

PMID: 35482533 PMC: 9157068. DOI: 10.1093/g3journal/jkac066.

Inherited human Apollo deficiency causes severe bone marrow failure and developmental defects.

Kermasson L, Churikov D, Awad A, Smoom R, Lainey E, Touzot F Blood. 2022; 139(16):2427-2440.

PMID: 35007328 PMC: 11022855. DOI: 10.1182/blood.2021010791.

A phosphate binding pocket is a key determinant of exo- versus endo-nucleolytic activity in the SNM1 nuclease family.

Baddock H, Newman J, Yosaatmadja Y, Bielinski M, Schofield C, Gileadi O Nucleic Acids Res. 2021; 49(16):9294-9309.

PMID: 34387694 PMC: 8450094. DOI: 10.1093/nar/gkab692.

The SNM1A DNA repair nuclease.

Baddock H, Yosaatmadja Y, Newman J, Schofield C, Gileadi O, McHugh P DNA Repair (Amst). 2020; 95:102941.

PMID: 32866775 PMC: 7607226. DOI: 10.1016/j.dnarep.2020.102941.

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