Trends in Cell Biology
ReviewCrosstalk between ubiquitin and other post-translational modifications on chromatin during double-strand break repair
Section snippets
The DSB response in the chromatin context
A DSB in DNA represents a difficult problem for any cell, and its proper repair is important for cell survival and the prevention of oncogenic translocations. In eukaryotes, an elaborate signaling pathway takes place on chromatin near the break site that coordinates ordered recruitment of specific factors, promotes DNA repair and cell cycle arrest. This response to DSBs (herein referred to as the DSB response) relies heavily on post-translational modifications of both chromatin components
Ubiquitination and SUMOylation
Similarly to ubiquitination, SUMOylation is catalyzed by a cascade of enzymes initiated by E1 SUMO-activating enzymes (SAE1 and SAE2), a single E2 conjugating enzyme (UBC9, ubiquitin-conjugating enzyme E2I), and various E3 SUMO ligases, which are considered to be important for target selection [16]. Established examples of SUMOylation regulating ubiquitination pathways have been known for many years [17], and indirect evidence suggested a role for SUMOylation in the DSB response 18, 19.
Ubiquitination and acetylation
Histone acetylation plays an important role in the regulation of chromatin structure [30], and therefore it is not surprising that specific histone acetyltransferases (HATs) play key roles in the DSB response. One major HAT, TIP60 (Tat interactive protein 60 kD; also known as lysine acetyltransferase 5, KAT5), was originally found to be part of a multimeric complex, and this seminal study demonstrated a role for TIP60 in DNA repair [31]. The activity of TIP60 as a regulator of chromatin
Ubiquitination and phosphorylation
As mentioned in the previous section, acetylation promotes RNF8 recruitment by activating the ATM kinase, which suggests crosstalk between ubiquitination and phosphorylation events during the DSB response. Not surprisingly, other crosstalk mechanisms between ubiquitination and phosphorylation also exist. Phosphorylation of MDC1 by these kinases promotes the recruitment of RNF8, which causes a feedback loop that promotes further ATM activation via RNF8 and another DSB response-associated E3
Ubiquitination and methylation
Although histone methylation is canonically associated with transcriptional regulation, early studies revealed an evolutionarily conserved role for histone H4K20 methylation in recruiting 53BP1 to DNA damage sites [44]. 53BP1 binds to this methylation mark via its tandem Tudor domains [45]. Although there are conflicting reports on which histone methyltransferase (HMTase) is primarily responsible for this modification 45, 46, 47, it is likely that many distinct HMTases contribute to H4K20
Ubiquitination and ADP-ribosylation
It is accepted that ADP-ribosylation plays a role in the DSB response, among many other signaling pathways [54]. Activation of poly(ADP-ribose) polymerase (PARP) enzymes is an early event in the DSB response [54], and recent work has demonstrated that ADP-ribosylation promotes the recruitment of multiple chromatin-modifying enzymes to damage sites 55, 56, 57. The most prominent of these is the CHD4/NuRD (chromodomain helicase DNA binding protein 4/nucleosome remodeling deacetylase) complex,
Concluding remarks
The molecular mechanisms involved in protein recruitment and activation during the DSB response are noticeably complex. The crosstalk mechanisms described here reflect only a small portion of this complexity, and crosstalk mechanisms that involve other modifications most definitely exist. For example, recent work has suggested that protein neddylation is also important for promoting ubiquitination events at sites of damage [63]. This complexity and various crosstalk mechanisms likely arose due
Acknowledgments
We wish to thank Barry Sleckman and Andrea Bredemeyer for critical reading and feedback on this manuscript. We also wish to thank the numerous scientists who have contributed significantly to our understanding of ubiquitination and its role in the DNA damage response, and we apologize that we could not cite all pertinent papers due to space limitations. This work was supported by the National Institutes of Health (NIH) National Cancer Institute (K08 CA158133), the American Cancer Society
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