Figure 1

Crosstalk between monoubiquitinated H2A (uH2A) and other histone modifications. Functional implications in transcription regulation (A-C), DNA damage response (D) and cell cycle progression (E) are illustrated. A. H3/H4 acetylation stimulates de-ubiquitination of uH2A by 2A-DUB in vitro, linking these modifications in the regulation of transcription. B. uH2A prevents H3K4 methylation by MLL3 in vitro. This is possibly one of the mechanisms by which uH2A negatively affects transcription initiation. C. Elevated global levels of uH2A correlate with low phosphorylation of linker histone H1, as observed upon knockdown of one of the H2A DUBs, 2A-DUB. Phosphorylation of H1 is thought to favor enhanced chromatin dissociation of this histone. uH2A might, by promoting/stabilizing H1 association with the nucleosome, diminish chromatin dynamics, thereby negatively affecting transcription. D. Histone phosphorylation and ubiquitination synergize in DNA damage signaling upon ionizing radiation (IR). Upon IR, phosphorylation of H2AX leads to recruitment and phosphorylation of MDC1. Phosphorylated MDC1 recruits RNF8 through its FHA domain. RNF8 subsequently polyubiquitinates H2A and H2AX. Also, TIP60-dependent acetylation of H2AX on K5 favors H2AX polyubiquitination upon IR. E. uH2A inhibits H3 S10 phosphorylation by AuroraB kinase in vitro, providing a potential mechanism for regulation of G2/M transition in vivo. The labels "Ub", "Ac", "Me" and "P" refer to monoubiquitination, acetylation, di- and trimethylation, and phosphorylation respectively.