In HeLa cells ChIP investigation at site specific I SceI caused DSBs demonstrates H4K20 Me1, H4K20 Me2, H4K20 Me3 all increase at the break site in association with a distinct accumulation of the WHSC1 histone methyltransferase, but only the increase in H4K20 Me2 and H4K20 Me3 is blocked by HC-030031 knockdown. Moreover, IR induced 53BP1 foci co localize with WHSC1 foci. Knockdown of WHSC1 increases cell sensitivity to killing by IR, confirming the biological importance of WHSC1 focus formation. Knockdown of WHSC1 also reduces the forming of IR induced 53BP1 foci however, not foci of the upstream elements gH2AX, MDC1, and RNF8. Accumulation of WHSC1 and H4K20 Me2 at DSBs needs gH2AX and MDC1 and occurs via an interaction of the BRCT areas of MDC1 with WHSC1 upon its IR caused phosphorylation at Ser102 by ATM. Low phosphorylatable WHSC1 is not recruited to DSBs and doesn’t help H4K20 Me2 deposition. WHSC1 knockdown cells reconstituted with the WHSC1S102A mutant protein show the same increased IR sensitivity as knockdown cells. Thus, these recent findings implicate DSB dependent de novo H4K20 methylation in recruiting 53BP1 to damaged internet sites in an ATM dependent manner. It’s noteworthy that the WHSC1 gene is defective in a developmental syndrome named Wolf Hirschhorn that has neurological and immunological impairment. Plastid One study indicates a high affinity interaction of 53BP1 with H3K79 Me2, but this finding isn’t established. Also, mouse dot1 null cells, which lack H3K79 Me2, show normal induction of 53BP1 and ATMS1981 G foci by IR. In fission yeast, Crb2, that will be structurally related but weakly conserved when compared with 53BP1, also binds H4K20 Me2. Budding yeasts and fission utilize H4K20 or H3K79 chromatin marks, respectively, for employment of Crb2 to DSBs. 53BP1 is directly for this Tp53 tumefaction suppressor and associated proteins in a reaction to DSBs, and the stability of Tp53 is decreased upon 53BP1 knockdown. Mechanistically, stabilization of Tp53 in reaction to DSBs is offered in part by a connection between the tandem Tudor domain of 53BP1 and the Lys382 dimethylated type of Tp53, which increases following DSB induction. Furthermore, in a knockout model and in human cells, DNp73b, an of the p53 like transcription factor p73, adversely adjusts equally Tp53 activation and ATM activation by directly interacting with 53BP1. DNp73b null mouse cells and tissues show increased levels of Tp53 and phosphorylated ATM in reaction Pemirolast ic50 to DSBs. However, overexpression of DNp73b in U2OS cells causes reduced IRinduced ATM phosphorylation and Tp53 accumulation. DNp73b interacts with 53BP1 and localizes to websites of DSBs, and knockdown of DNp73 causes enhanced focus formation of gH2AX and 53BP1 after IR coverage, consistent with enhanced ATM initial. Hence, DNp73b down handles ATM mediated DSB repair and thereby functions to prevent neurodegeneration and Tp53 dependent apoptosis in other areas and mouse thymocytes, see discussion in.