Savic, Velibor, Yin, Bu, Maas, Nancy L, Bredemeyer, Andrea L, Carpenter, Andrea C, Helmink, Beth A, Yang-Iott, Katherine S, Sleckman, Barry P and Bassing, Craig H (2009) Formation of dynamic gamma-H2AX domains along broken DNA strands is distinctly regulated by ATM and MDC1 and dependent upon H2AX densities in chromatin. Molecular Cell, 34 (3). pp. 298-310. ISSN 1097-2765

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Abstract

A hallmark of the cellular response to DNA double-strand breaks (DSBs) is histone H2AX phosphorylation in chromatin to generate gamma-H2AX. Here, we demonstrate that gamma-H2AX densities increase transiently along DNA strands as they are broken and repaired in G1 phase cells. The region across which gamma-H2AX forms does not spread as DSBs persist; rather, gamma-H2AX densities equilibrate at distinct levels within a fixed distance from DNA ends. Although both ATM and DNA-PKcs generate gamma-H2AX, only ATM promotes gamma-H2AX formation to maximal distance and maintains gamma-H2AX densities. MDC1 is essential for gamma-H2AX formation at high densities near DSBs, but not for generation of gamma-H2AX over distal sequences. Reduced H2AX levels in chromatin impair the density, but not the distance, of gamma-H2AX formed. Our data suggest that H2AX fuels a gamma-H2AX self-reinforcing mechanism that retains MDC1 and activated ATM in chromatin near DSBs and promotes continued local phosphorylation of H2AX

Item Type:	Article
Schools and Departments:	Brighton and Sussex Medical School > Clinical and Experimental Medicine
Subjects:	Q Science > QH Natural history > QH0301 Biology > QH0426 Genetics > QH0447 Genes. Alleles. Genome Q Science > QH Natural history > QH0301 Biology Q Science > QH Natural history > QH0301 Biology > QH0426 Genetics > QH0460 Mutations
Depositing User:	Velibor Savic
Date Deposited:	11 Feb 2013 14:27
Last Modified:	14 May 2015 09:35
URI:	http://srodev.sussex.ac.uk/id/eprint/43581

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