Kusch T, Florens L, Macdonald WH, Swanson SK, Glaser RL, Yates III JR et al.. Acetylation by tip60 is required for selective histone variant exchange at DNA lesions. Science 306: 2084-2087

Stowers Institute for Medical Research, Kansas City, Kansas, United States
Science (Impact Factor: 33.61). 01/2005; 306(5704):2084-7. DOI: 10.1126/science.1103455
Source: PubMed


Phosphorylation of the human histone variant H2A.X and H2Av, its homolog in Drosophila melanogaster, occurs rapidly at sites of DNA double-strand breaks. Little is known about the function of this phosphorylation or its removal
during DNA repair. Here, we demonstrate that the Drosophila Tip60 (dTip60) chromatin-remodeling complex acetylates nucleosomal phospho-H2Av and exchanges it with an unmodified H2Av.
Both the histone acetyltransferase dTip60 as well as the adenosine triphosphatase Domino/p400 catalyze the exchange of phospho-H2Av.
Thus, these data reveal a previously unknown mechanism for selective histone exchange that uses the concerted action of two
distinct chromatin-remodeling enzymes within the same multiprotein complex.

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    • "Chromatin is a highly dynamic structure that is actively remodeled during intrinsic changes such as cell cycle or developmental progression and responds to external cues, such as DNA damage . In response to DNA damage, chromatin-remodeling factors regulate the access of repair proteins to DNA, participate in checkpoint signaling, and contribute to the actual DNA repair process (Kusch et al., 2004; Osley et al., 2007; Soria et al., 2012). For instance, the noncatalytic subunit of the nucleosome remodeling complex chromatin accessibility complex (CHRAC), ACF1, is required for DNA double-stranded break (DSB) repair in human cells and regulates the G2-M checkpoint (Lan et al., 2010; Sá nchez-Molina et al., 2011). "
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    ABSTRACT: Chromatin reorganization and the incorporation of specific histone modifications during DNA damage response are essential steps for the successful repair of any DNA lesion. Here, we show that the histone-fold protein CHRAC14 plays an essential role in response to DNA damage in Drosophila. Chrac14 mutants are hypersensitive to genotoxic stress and do not activate the G2/M cell-cycle checkpoint after damage induction. Even though the DNA damage repair process is activated in the absence of CHRAC14, lesions are not repaired efficiently. In the absence of CHRAC14, the centromere-specific histone H3 variant CENP-A localizes to sites of DNA damage, causing ectopic kinetochore formation and genome instability. CENP-A and CHRAC14 are able to interact upon damage. Our data suggest that CHRAC14 modulates chromatin composition in response to DNA damage, which is required for efficient DNA damage repair in Drosophila.
    Full-text · Article · Apr 2014 · Cell Reports
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    • "This is consistent with the idea of the two proteins, reptin and Mrg15, working in the same complex. In Drosophila, Mrg15 and reptin proteins have been copurified and also show similar genetic interactions in position-effect variegation (Kusch et al. 2004; Qi et al. 2006). Interestingly, the reptin protein and its binding partner pontin, also known as RVB2/RVB1, may have DNA/RNA-binding functions and participate in a variety of chromatin-remodeling complexes (Jha and Dutta 2009), further linking condensins and Mrg15 to chromatin-and histone-modifying activities. "
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    ABSTRACT: Dynamic regulation of chromosome structure and organization is critical for fundamental cellular processes such as gene expression and chromosome segregation. Condensins are conserved chromosome associated proteins that regulate a variety of chromosome dynamics, including axial shortening, lateral compaction and homolog pairing. However, how the in vivo activities of condensins are regulated and how functional interactors that may target condensins to chromatin are not well understood. To better understand how Drosophila melanogaster condensin is regulated we performed a yeast two-hybrid screen and identified the chromo-barrel domain protein Mrg15 to interact with the Cap-H2 condensin subunit. Genetic interactions demonstrate that Mrg15 function is required for Cap-H2 mediated unpairing of polytene chromosomes in ovarian nurse cells and salivary gland cells. In diploid tissues, transvection assays demonstrate that Mrg15 inhibits transvection at Ubx and cooperates with Cap-H2 to antagonize transvection at yellow. In cultured cells we show that levels of chromatin bound Cap-H2 protein are partially dependent on Mrg15 and Cap-H2 mediated homolog unpairing is suppressed by RNAi depletion of Mrg15. Thus, maintenance of interphase chromosome compaction and homolog pairing status requires both Mrg15 and Cap-H2. We propose a model where the Mrg15 and Cap-H2 protein-protein interaction may serve to recruit Cap-H2 to chromatin and facilitates compaction of interphase chromatin.
    Full-text · Article · Jul 2013 · Genetics
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    • "SLX2 might be involved in molecular events before the full establishment of SC based on its co-localization with γH2AX and its interaction with TIP60. While γH2AX is a marker for DSBs and their subsequent repairs (Celeste et al., 2002; Turner et al., 2004, 2005), TIP60 interacts with a variety of transcription factors and chromatin-remodeling complexes to facilitate DSBs repair (Ai et al., 2007; Auger et al., 2008; DeRan et al., 2008; Jha et al., 2008; Kusch et al., 2004; Yamagata and Kitabayashi, 2009). We tested whether SLX2 physically interacts with γH2AX, but could not detect an interaction (data not shown). "
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    ABSTRACT: Meiosis is the process by which diploid germ cells produce haploid gametes. A key event is the formation of the synaptonemal complex. In the pachytene stage, the unpaired regions of X and Y chromosomes form a specialized structure, the XY body, within which gene expression is mostly silenced. In the present study, we showed that SYCP3-like X-linked 2 (SLX2, 1700013H16Rik), a novel member of XLR (X-linked Lymphocyte-Regulated) family, was specifically expressed in meiotic germ cells. In the spermatocyte SLX2 was distributed in the nucleus of germ cells at the preleptotene, leptotene and zygotene stages and is then restricted to the XY body at the pachytene stage. This localization change is coincident with that of phosphorylated histone H2AX (γH2AX), a well-known component of the sex body. Through yeast two-hybrid screening and coimmunoprecipitation assays, we demonstrated that SLX2 interacts with synaptonemal complex central element protein 2 (SYCE2), an important component of synaptonemal complex, and histone acetyltransferase TIP60, which has been implicated in remodeling phospho-H2AX-containing nucleosomes at sites of DNA damage. These results suggest that SLX2 might be involved in DNA recombination, synaptonemal complex formation as well as sex body maintenance during meiosis.
    Full-text · Article · Jun 2013 · Gene
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