MutS homologue hMSH5: recombinational DSB repair and non-synonymous polymorphic variants

Xiling Wu; Yang Xu; Katey Feng; Joshua D Tompkins; Chengtao Her

doi:10.1371/journal.pone.0073284

Back

MutS homologue hMSH5: recombinational DSB repair and non-synonymous polymorphic variants

Journal article

Open access

MutS homologue hMSH5: recombinational DSB repair and non-synonymous polymorphic variants

Xiling Wu, Yang Xu, Katey Feng, Joshua D Tompkins and Chengtao Her

PloS one, Vol.8(9), pp.e73284-e73284

2013

DOI: https://doi.org/10.1371/journal.pone.0073284

Handle:

https://hdl.handle.net/2376/110575

PMCID: PMC3762724

PMID: 24023853

Files and links (1)

url

https://doi.org/10.1371/journal.pone.0073284View

Published (Version of record) Open

Abstract

Rad51 Recombinase - metabolism

Cell Survival - drug effects

DNA Repair - drug effects

Homologous Recombination - drug effects

Humans

Cell Cycle Proteins - metabolism

Cell Survival - genetics

DNA Repair - genetics

Polymorphism, Genetic

DNA-Binding Proteins - metabolism

MRE11 Homologue Protein

DNA Breaks, Double-Stranded - drug effects

HEK293 Cells

Cell Cycle Proteins - genetics

Antineoplastic Agents - pharmacology

Mutation

Chromatin - drug effects

Chromatin - genetics

Double-strand breaks (DSBs) constitute the most deleterious form of DNA lesions that can lead to genome alterations and cell death, and the vast majority of DSBs arise pathologically in response to DNA damaging agents such as ionizing radiation (IR) and chemotherapeutic agents. Recent studies have implicated a role for the human MutS homologue hMSH5 in homologous recombination (HR)-mediated DSB repair and the DNA damage response. In the present study, we show that hMSH5 promotes HR-based DSB repair, and this property resides in the carboxyl-terminal portion of the protein. Our results demonstrate that DSB-triggered hMSH5 chromatin association peaks at the proximal regions of the DSB and decreases gradually with increased distance from the break. Furthermore, the DSB-triggered hMSH5 chromatin association is preceded by and relies on the assembly of hMRE11 and hRad51 at the proximal regions of the DSB. Lastly, the potential effects of hMSH5 non-synonymous variants (L85F, Y202C, V206F, R351G, L377F, and P786S) on HR and cell survival in response to DSB-inducing anticancer agents have been analyzed. These experiments show that the expression of hMSH5 variants elicits different survival responses to anticancer drugs cisplatin, bleomycin, doxorubicin and camptothecin. However, the effects of hMSH5 variants on survival responses to DSB-inducing agents are not directly correlated to their effects exerted on HR-mediated DSB repair, suggesting that the roles of hMSH5 variants in the processes of DNA damage response and repair are multifaceted.

Metrics

11 Record Views

Details

Title: MutS homologue hMSH5: recombinational DSB repair and non-synonymous polymorphic variants
Creators: Xiling Wu - School of Molecular Biosciences, College of Veterinary Medicine, Washington State University, Pullman, Washington, United States of America
Yang Xu
Katey Feng
Joshua D Tompkins
Chengtao Her
Publication Details: PloS one, Vol.8(9), pp.e73284-e73284
Academic Unit: Molecular Biosciences, School of
Publisher: United States
Grant note: R01 GM084353 / NIGMS NIH HHS GM084353 / NIGMS NIH HHS
Identifiers: 99900547160201842
Language: English
Resource Type: Journal article