Deregulation of DNA double-strand break repair in multiple myeloma: implications for genome stability

PloS One
Ana B HerreroNorma C Gutierrez

Abstract

Multiple myeloma (MM) is a hematological malignancy characterized by frequent chromosome abnormalities. However, the molecular basis for this genome instability remains unknown. Since both impaired and hyperactive double strand break (DSB) repair pathways can result in DNA rearrangements, we investigated the functionality of DSB repair in MM cells. Repair kinetics of ionizing-radiation (IR)-induced DSBs was similar in MM and normal control lymphoblastoid cell lines, as revealed by the comet assay. However, four out of seven MM cell lines analyzed exhibited a subset of persistent DSBs, marked by γ-H2AX and Rad51 foci that elicited a prolonged G2/M DNA damage checkpoint activation and hypersensitivity to IR, especially in the presence of checkpoint inhibitors. An analysis of the proteins involved in DSB repair in MM cells revealed upregulation of DNA-PKcs, Artemis and XRCC4, that participate in non-homologous end joining (NHEJ), and Rad51, involved in homologous recombination (HR). Accordingly, activity of both NHEJ and HR were elevated in MM cells compared to controls, as determined by in vivo functional assays. Interestingly, levels of proteins involved in a highly mutagenic, translocation-promoting, alternative NHEJ subpathway...Continue Reading

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Citations

Nov 19, 2015·BioMed Research International·Antonia CagnettaMichele Cea
Jan 18, 2017·Mutagenesis·Luíza Araújo da Costa XavierViviane Souza do Amaral
Mar 7, 2020·Journal of Cellular and Molecular Medicine·Ana Belén HerreroNorma C Gutiérrez
Jun 6, 2017·Frontiers in Oncology·Ana Belén Herrero, Norma Carmen Gutiérrez
May 11, 2019·Scientific Reports·Hiroyuki YamazakiAkifumi Takaori-Kondo
Aug 6, 2019·Frontiers in Oncology·Ismail S Mohiuddin, Min H Kang
Dec 22, 2020·Expert Opinion on Therapeutic Patents·Suwen HuTian Xie
Nov 3, 2020·Journal of Medicinal Chemistry·Samuel H MyersAndrea Cavalli
May 1, 2021·Neoplasia : an International Journal for Oncology Research·María Ovejero-SánchezAna Belén Herrero
Mar 21, 2020·Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation·Pritesh R PatelDamiano Rondelli

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Methods Mentioned

BETA
flow cytometry
electrophoresis
transfection
transfections
PCR
flow

Software Mentioned

sofWoRx
ImageJ
Simfit
OpenComet

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