SETD2 is required for DNA double-strand break repair and activation of the p53-mediated checkpoint

Abstract

Histone modifications establish the chromatin states that coordinate the DNA damage response. In this study, we show that SETD2, the enzyme that trimethylates histone H3 lysine 36 (H3K36me3), is required for ATM activation upon DNA double-strand breaks (DSBs). Moreover, we find that SETD2 is necessary for homologous recombination repair of DSBs by promoting the formation of RAD51 presynaptic filaments. In agreement, SETD2-mutant clear cell renal cell carcinoma (ccRCC) cells displayed impaired DNA damage signaling. However, despite the persistence of DNA lesions, SETD2-deficient cells failed to activate p53, a master guardian of the genome rarely mutated in ccRCC and showed decreased cell survival after DNA damage. We propose that this novel SETD2-dependent role provides a chromatin bookmarking instrument that facilitates signaling and repair of DSBs. In ccRCC, loss of SETD2 may afford an alternative mechanism for the inactivation of the p53-mediated checkpoint without the need for additional genetic mutations in TP53.DOI: http://dx.doi.org/10.7554/eLife.02482.001

Loss of SETD2, but not H3K36me3, correlates with aggressive clinicopathological features of clear cell renal cell carcinoma patients

“…SETD2 protein is responsible for H3K36me3, which may lead to chromatin accessibility changes (23,24) and hinder mismatch repair (MMR) (25), and eventually cause RNA processing defects and promote oncogenesis (26). Previous studies support SETD2's role as a tumor suppressor in ccRCC (27). In our present study, low SETD2 expression was found to be associated with an aggressive phenotype of ccRCC, and was identified as an independent prognostic factor in two independent ccRCC cohorts.…”

DNA double strand break repair pathway choice: a chromatin based decision?

“…Furthermore, SETD2 depletion seemed to favor repair by MMEJ. 24 Importantly, neither SETD2 recruitment nor increased H3K36me3 levels were found at DSBs, [22][23][24][25] suggesting that pre-established H3K36me3 channels active genes to HR repair. Notably, we found that RAD51 recruitment at HR-prone DSBs also depends on the lens epithelium-derived growth factor (LEDGF)/p75, which possesses a PWWP domain for H3K36me3-recognition.…”

“…Indeed, we showed that depletion of the main H3K36me3 histone methyltransferase, SETD2, 18 is necessary for HR repair of "HR-prone" DSBs. 22 Concomitantly, 2 other groups reported the critical function of human SETD2 in homologous recombination 23,24 using other experimental systems such as I-SceIand radiation-induced DSBs. Furthermore, SETD2 depletion seemed to favor repair by MMEJ.…”

The epigenetic landscape of renal cancer

“…This histone methylation is associated with open heterochromatin and reduced CpG methylation 159,158 , and changes in heterochromatin structure (such as nucleosome rearrangement) can alter the accessibility of the spliceosome machinery to genes and alter the expression of splice-variants. SETD2 mutations could, therefore, change the expression levels and functional structure of many genes 160 . H3K36Me3 is required for serine-protein kinase ATM and TP53-mediated DNA damage checkpoint activation 161 and the recruitment of the DNA mismatch repair protein Msh2 (also called hMutSα) 162 , suggesting that loss of SETD2 function combined with PBRM1 mutations could increase genomic instability and prevent correct cell-cycle checkpoint control.…”