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Ubiquitylation of histones at sites of DNA damage

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Abstract:

A compromised DNA damage response leads to genomic instability, which is one of the hallmarks of cancer. Conversely, the DNA damage response is activated in cancer cells subjected to chemo- and radio therapy. One of the most striking features of the cellular response to DNA double strand breaks (DSBs) is the accumulation of proteins into large and microscopically discernible structures in the vicinity of the lesions – the so-called ionizing radiation induced foci (IRIF). This accumulation process requires post-translational modifications of chromatin, such as the phosphorylation of the histone variant H2AX by the ATM kinase (γ-H2AX). Recently, we discovered an additional de novo histone modification at sites of DNA damage, namely the ubiquitylation of the core histones H2A and H2AX. This modification is carried out by a complex of proteins containing among other the Mdc1 adaptor protein and the RNF8 ubiquitin ligase. The complex is both assembled and targeted to the sites of DNA damage by multiple ATM phosphorylation events.

We have previously shown that proteins accumulate in IRIF in two distinct kinetic waves. The first wave comprises the γ-H2AX binding protein Mdc1 and proteins that physically interact with Mdc1, such as RNF8 and Nbs1. During the second wave, initiated 1–2 minutes after the first wave, proteins such as 53BP1 and BRCA1 accumulate. We can now show that histone ubiquitylation couples these two waves and that the presence of active RNF8 at sites of DNA damage is required for the accumulation of late factors such as 53BP1 and BRCA1.

The ability of cells to locally ubiquitylate histones determines the survival of cells to ionizing radiation and thus the outcome of the DNA damage response. Given the potential to pharmacologically inhibit this activity, our findings may eventually provide a means to modulate the ability of cancer cells to respond to chemo- and radio therapy.

Document Type: Abstract

DOI: http://dx.doi.org/10.1111/j.1600-0463.2008.001165_15.x

Affiliations: Institut for Kræftbiologi og Forskningscenteret for Gentoksisk Stress, Kræftens Bekæmpelse, Strandboulevarden 49, 2100 København Ø

Publication date: May 1, 2008

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