Differential requirement for H2AX and 53BP1 in organismal development and genome maintenance in the absence of poly(ADP)ribosyl polymerase 1

Benjamin Orsburn, Beatriz Escudero, Mansi Prakash, Silvia Gesheva, Guosheng Liu, David L. Huso, Sonia Franco

Research output: Contribution to journalArticle

Abstract

Combined deficiencies of poly(ADP)ribosyl polymerase 1 (PARP1) and ataxia telangiectasia mutated (ATM) result in synthetic lethality and, in the mouse, early embryonic death. Here, we investigated the genetic requirements for this lethality via analysis of mice deficient for PARP1 and either of two ATM-regulated DNA damage response (DDR) factors: histone H2AX and 53BP1. We found that, like ATM, H2AX is essential for viability in a PARP1-deficient background. In contrast, deficiency for 53BP1 modestly exacerbates phenotypes of growth retardation, genomic instability, and organismal radiosensitivity observed in PARP1-deficient mice. To gain mechanistic insights into these different phenotypes, we examined roles for 53BP1 in the repair of replication-associated double-strand breaks (DSBs) in several cellular contexts. We show that 53BP1 is required for DNA-PKcs-dependent repair of hydroxyurea (HU)-induced DSBs but dispensable for RPA/RAD51-dependent DSB repair in the same setting. Moreover, repair of mitomycin C (MMC)-induced DSBs and sister chromatid exchanges (SCEs), two RAD51-dependent processes, are 53BP1 independent. Overall, our findings define 53BP1 as a main facilitator of nonhomologous end joining (NHEJ) during the S phase of the cell cycle, beyond highly specialized lymphocyte rearrangements. These findings have important implications for our understanding of the mechanisms whereby ATM-regulated DDR prevents human aging and cancer.

Original languageEnglish (US)
Pages (from-to)2341-2352
Number of pages12
JournalMolecular and Cellular Biology
Volume30
Issue number10
DOIs
StatePublished - May 2010

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Ataxia Telangiectasia
Adenosine Diphosphate
Maintenance
Genome
DNA Damage
Phenotype
Sister Chromatid Exchange
Hydroxyurea
Genomic Instability
Radiation Tolerance
Mitomycin
S Phase
Histones
Cell Cycle
Lymphocytes
DNA
Growth
Neoplasms

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Differential requirement for H2AX and 53BP1 in organismal development and genome maintenance in the absence of poly(ADP)ribosyl polymerase 1. / Orsburn, Benjamin; Escudero, Beatriz; Prakash, Mansi; Gesheva, Silvia; Liu, Guosheng; Huso, David L.; Franco, Sonia.

In: Molecular and Cellular Biology, Vol. 30, No. 10, 05.2010, p. 2341-2352.

Research output: Contribution to journalArticle

Orsburn, Benjamin ; Escudero, Beatriz ; Prakash, Mansi ; Gesheva, Silvia ; Liu, Guosheng ; Huso, David L. ; Franco, Sonia. / Differential requirement for H2AX and 53BP1 in organismal development and genome maintenance in the absence of poly(ADP)ribosyl polymerase 1. In: Molecular and Cellular Biology. 2010 ; Vol. 30, No. 10. pp. 2341-2352.
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