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

  1. Sílvia Carvalho
  2. Alexandra C Vítor
  3. Sreerama C Sridhara
  4. Filipa B Martins
  5. Ana C Raposo
  6. Joana MP Desterro
  7. João Ferreira
  8. Sérgio F de Almeida  Is a corresponding author
  1. Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Portugal

Abstract

Histone modifications establish the chromatin states that coordinate the DNA damage response. Here, 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.

Article and author information

Author details

  1. Sílvia Carvalho

    Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal
    Competing interests
    The authors declare that no competing interests exist.
  2. Alexandra C Vítor

    Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal
    Competing interests
    The authors declare that no competing interests exist.
  3. Sreerama C Sridhara

    Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal
    Competing interests
    The authors declare that no competing interests exist.
  4. Filipa B Martins

    Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal
    Competing interests
    The authors declare that no competing interests exist.
  5. Ana C Raposo

    Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal
    Competing interests
    The authors declare that no competing interests exist.
  6. Joana MP Desterro

    Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal
    Competing interests
    The authors declare that no competing interests exist.
  7. João Ferreira

    Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal
    Competing interests
    The authors declare that no competing interests exist.
  8. Sérgio F de Almeida

    Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal
    For correspondence
    sergioalmeida@fm.ul.pt
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Joaquin M Espinosa, University of Colorado, United States

Version history

  1. Received: February 6, 2014
  2. Accepted: April 30, 2014
  3. Accepted Manuscript published: May 6, 2014 (version 1)
  4. Version of Record published: June 3, 2014 (version 2)

Copyright

© 2014, Carvalho et al.

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

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  1. Sílvia Carvalho
  2. Alexandra C Vítor
  3. Sreerama C Sridhara
  4. Filipa B Martins
  5. Ana C Raposo
  6. Joana MP Desterro
  7. João Ferreira
  8. Sérgio F de Almeida
(2014)
SETD2 is required for DNA double-strand break repair and activation of the p53-mediated checkpoint
eLife 3:e02482.
https://doi.org/10.7554/eLife.02482

Share this article

https://doi.org/10.7554/eLife.02482

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