Elsevier

DNA Repair

Volume 8, Issue 7, 4 July 2009, Pages 873-876
DNA Repair

Hot Topics in DNA Repair
Histone H2A.X Tyr142 phosphorylation: A novel sWItCH for apoptosis?

https://doi.org/10.1016/j.dnarep.2009.04.003Get rights and content

Abstract

Histone H2A.X phosphorylation on Ser139 in response to DNA damage is the major signal for the assembly of the so-called γH2A.X chromatin domain, a region surrounding an unrepaired DNA double-strand break that is characterized by the accumulation of a large number of DNA damage response proteins. However, it is not yet clear how this event is regulated in space and time. The recent discovery of H2A.X Tyr142 phosphorylation by the WICH complex and its dephosphorylation by the EYA1/3 phosphatases may provide substantial novel insight into this process. WSTF, a subunit of the WICH complex bears a novel kinase domain at its N-terminus that constitutively targets H2A.X on Tyr142. This novel histone modification appears to determine the relative recruitment of either DNA repair or pro-apoptotic factors to sites of DNA damage. Thus, the balance of H2A.X Tyr142 phosphorylation/dephosphorylation may constitute a novel switch mechanism to determine cell fate after DNA damage.

Introduction

DNA double-strand breaks (DSBs) are highly toxic lesions that, if unrepaired or repaired incorrectly, can cause cell death, mutations and chromosomal translocations, and can lead to cancer. Cells react to DSBs by rapidly deploying a host of proteins to the damaged chromatin regions. Some of these factors engage in DNA repair, while others trigger a signaling pathway (called the DNA damage checkpoint) that delays cell cycle progression and coordinates repair processes; together these events comprise the DNA damage response (DDR [1]). Some DDR factors have intrinsic affinity for free DNA ends, while others accumulate in large nuclear aggregates that appear as ionizing radiation-induced nuclear foci (IRIF) by fluorescence microscopy.

A key regulator of IRIF formation in mammalian cells is the histone H2A variant, H2A.X, a component of the nucleosome core structure that comprises 10–15% of total cellular H2A in higher organisms [2]. H2A.X is phosphorylated extensively on a conserved serine residue (Ser139) near its carboxyl-terminus (C-terminus) in chromatin regions bearing DSBs, and this is mediated by members of the phosphoinositide-3-kinase-related protein kinase (PIKK) family [3]. Cells isolated from H2A.X deficient mice exhibit radiation-induced chromosomal aberrations, indicating that H2A.X is involved in the signaling and/or repair of DSBs [4], [5]. Indeed, H2A.X modulates both homologous recombination (HR) and non-homologous end joining (NHEJ) pathways of DSB repair, although it is not an essential component of either [4], [5], [6], [7]. H2A.X phosphorylated on Ser139 (termed γH2A.X) is recognized by MDC1, a large mediator protein, which through its BRCT domains directly associates with γH2A.X. MDC1 coordinates the hierarchical assembly of DDR proteins on damaged chromatin by recruiting various factors into these areas. Moreover, MDC1 also regulates formation and maintenance of the γH2A.X chromatin domain either by promoting Ser139 phosphorylation or by preventing its dephosphorylation (or both) [8]. However, several aspects of γH2A.X regulation are not yet understood. For example, it is not known how this modification is restricted to the damaged chromosomes and does not extend into neighboring undamaged chromosomes. Moreover, it is also not yet clear how the disassembly of the γH2A.X chromatin domain is regulated, once DSB repair is completed. Finally, recent evidence suggests that local chromatin structure surrounding a DSB greatly influences the stability of the γH2A.X chromatin domain: in euchromatic regions, γH2A.X foci seem to disappear more rapidly than in heterochromatic regions [9]. This may reflect the need for more extensive and intricate chromatin structure modulations to accurately repair DSBs in heterochromatic regions.

Section snippets

A novel H2A.X modification

In two recent Nature articles [10], [11], the Allis and Rosenfeld laboratories describe a novel histone H2A.X modification: the phosphorylation of Tyr142. This residue is targeted by WSTF, a member of the BAZ/WAL family of chromatin remodeling factors that, together with SNF2H (a mammalian homologue of the ISWI ATPase), forms the WICH complex [12], [13]. WICH (WSTF-ISWI ATP-dependent chromatin-remodeling complex), is capable to mobilize nucleosomes in vitro and appears to stably associate with

Possible mechanisms of γH2A.X regulation

Surprisingly, Allen and coworkers also showed that Ser139 phosphorylation partially depends on Tyr142 phosphorylation. In the absence of Tyr142 phosphorylation (i.e. upon silencing of WSTF expression by RNA interference) Ser139 phosphorylation is also compromised [10]. This is a bit difficult to comprehend because on the one hand, DNA damage leads to Tyr142 dephosphorylation while on the other hand this modification seems to be necessary for H2A.X Ser139 phosphorylation. At first glance, it may

What is the physiological role of H2A.X Tyr142 phosphorylation?

As outlined in the last two sections, Tyr142 phosphorylation appears to prevent the establishment of the γH2A.X chromatin domain. But what is the physiological role of this modification? One would expect that if the γH2A.X chromatin domain could not be efficiently assembled and maintained, cells would display defects in DSB repair and/or checkpoint activation and ultimately, suffer from genome instability. Unfortunately, neither the Allis nor the Rosenfeld labs addressed this important issue.

Conclusions

The discovery of novel histone modifications usually initiate a major leap forward in our understanding of how cells regulate DNA metabolic events such as transcription, DNA replication and repair. Surely, the discovery of H2A.X Tyr142 phosphorylation and its regulation by the WICH complex and the EYA phosphatases will not mark an exception of this rule of thumb. However, at the moment the picture is still rather murky. While it is clear that irradiation triggers Tyr142 dephosphorylation within

Conflict of interest

None.

Acknowledgements

Many thanks to Jiri Lukas for critical reading of the manuscript. Research in the Stucki lab is supported by the Swiss National Foundation, UBS AG ‘im Auftrag eines Kunden’ and by the Canton of Zürich.

Cited by (32)

  • Cyclin F-Mediated Degradation of SLBP Limits H2A.X Accumulation and Apoptosis upon Genotoxic Stress in G2

    2016, Molecular Cell
    Citation Excerpt :

    H2A.X (encoded by the H2AFX gene) evolved as a unique gene in vertebrates, and its phosphorylation on Ser139 (S139), denoted γH2A.X, plays a critical role in the repair of double-stranded DNA breaks (DSBs) (reviewed in Harper and Elledge, 2007). Additionally, phosphorylation of H2A.X on Tyr142 (Y142) in conjunction with phosphorylated S139 recruits the pro-apoptotic factor JNK1 upon DNA damage (Cook et al., 2009; reviewed in Stucki, 2009). Although transcription of canonical histone mRNAs is limited to late G1 and S, H2AFX mRNA is transcribed during every phase of the cell cycle.

View all citing articles on Scopus
View full text