Evidence for a direct involvement of hMSH5 in promoting ionizing radiation induced apoptosis

Joshua D Tompkins; Xiling Wu; Yen-Lin Chu; Chengtao Her

doi:10.1016/j.yexcr.2009.05.004

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Evidence for a direct involvement of hMSH5 in promoting ionizing radiation induced apoptosis

Journal article

Open access

Peer reviewed

Evidence for a direct involvement of hMSH5 in promoting ionizing radiation induced apoptosis

Joshua D Tompkins, Xiling Wu, Yen-Lin Chu and Chengtao Her

Experimental cell research, Vol.315(14), pp.2420-2432

08/15/2009

DOI: https://doi.org/10.1016/j.yexcr.2009.05.004

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https://hdl.handle.net/2376/108923

PMCID: PMC3171649

PMID: 19442657

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https://doi.org/10.1016/j.yexcr.2009.05.004View

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Abstract

Phosphorylation - physiology

Tumor Suppressor Proteins - metabolism

Apoptosis - radiation effects

Humans

Cell Cycle Proteins - metabolism

Nuclear Proteins - metabolism

DNA-Binding Proteins - metabolism

Amino Acid Motifs - physiology

Tumor Protein p73

Transfection

Cell Line, Tumor

Proto-Oncogene Proteins c-abl - metabolism

Recombination, Genetic - radiation effects

Apoptosis - physiology

HeLa Cells

DNA Damage - radiation effects

Radiation, Ionizing

Although increasing evidence has suggested that the hMSH5 protein plays an important role in meiotic and mitotic DNA recombinational repair, its precise functions in recombination and DNA damage response are presently elusive. Here we show that the interaction between hMSH5 and c-Abl confers ionizing radiation (IR)-induced apoptotic response by promoting c-Abl activation and p73 accumulation, and these effects are greatly enhanced in cells expressing hMSH5(P29S) (i.e. the hMSH5 variant possessing a proline to serine change within the N-terminal (Px)(5) dipeptide repeat). Our current study provides the first evidence that the (Px)(5) dipeptide repeat plays an important role in modulating the interaction between hMSH5 and c-Abl and alteration of this dipeptide repeat in hMSH5(P29S) leads to increased IR sensitivity owing to enhanced caspase-3-mediated apoptosis. In addition, RNAi-mediated hMSH5 silencing leads to the reduction of apoptosis in IR-treated cells. In short, this study implicates a role for hMSH5 in DNA damage response involving c-Abl and p73, and suggests that mutations impairing this process could significantly affect normal cellular responses to anti-cancer treatments.

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Title: Evidence for a direct involvement of hMSH5 in promoting ionizing radiation induced apoptosis
Creators: Joshua D Tompkins - School of Molecular Biosciences and Center for Reproductive Biology, PO Box 644660, Washington State University, Pullman, WA 99164-4660, USA
Xiling Wu
Yen-Lin Chu
Chengtao Her
Publication Details: Experimental cell research, Vol.315(14), pp.2420-2432
Academic Unit: Molecular Biosciences, School of
Publisher: United States
Grant note: R01 CA101796-04 / NCI NIH HHS CA101796 / NCI NIH HHS R01 CA101796 / NCI NIH HHS
Identifiers: 99900547193601842
Language: English
Resource Type: Journal article