Fig 1.
Chromatin dynamics in response to double strand break (DSB) formation.
The MRN complex rapidly senses DNA breaks and, together with TIP60 acetyltransferase, recruits and activates the ATM kinase through auto-phosphorylation on Ser1981 (depicted as P) and acetylation (depicted as Ac), respectively. ATM initiates a signaling cascade by phosphorylation of histone H2AX on Ser139, forming γH2AX at the DNA lesion (depicted as γ). γH2AX serves as a docking site for recruitment of the scaffolding protein MDC1. MDC1 is phosphorylated by ATM and recruits multiple DDR factors. MDC1 recruits the MRN complex through binding of Nbs1, allowing further recruitment of ATM and the spread of γH2AX away from the DSB site. MDC1 also recruits the Nu4A complex, consisting of the p400 SWI/SNF ATPase and TIP60, which allows for acetylation of histone H4K16. Phospho-MDC1 serves as a docking site for the ubiquitin ligase RNF8, which ubiquitylates H2A/H2AX (depicted as U). Ubiquitylation triggers recruitment of the ubiquitin ligase RNF168, which binds and amplifies the ubiquitin conjugates initiated by RNF8, resulting in the loading of BRCA1 and 53BP1, which participate in DSB repair. 53BP1 is a bivalent histone code reader whose stable retention at DSBs requires the recognition of the DNA damage inducible mark H2AK15ub as well as nucleosomes modified with H3K20me2 (depicted as me2) [30]. The recruitment of SIRT1 and SIRT6 stimulates HR factor recruitment, while recruitment of HDAC1 and HDAC2 promotes recruitment of NHEJ factors.