Zinc finger protein ZNF384 is an adaptor of Ku to DNA during classical non-homologous end-joining

Classical non-homologous end-joining (cNHEJ) is the dominant pathway used by human cells to repair DNA double-strand breaks (DSBs) and maintain genome stability. Here the authors show that PARP1-driven chromatin expansion allows the recruitment of ZNF384, which in turn recruits Ku70/Ku80 to facilitate cNHEJ.DNA double-strand breaks (DSBs) are among the most deleterious types of DNA damage as they can lead to mutations and chromosomal rearrangements, which underlie cancer development. Classical non-homologous end-joining (cNHEJ) is the dominant pathway for DSB repair in human cells, involving the DNA-binding proteins XRCC6 (Ku70) and XRCC5 (Ku80). Other DNA-binding proteins such as Zinc Finger (ZnF) domain-containing proteins have also been implicated in DNA repair, but their role in cNHEJ remained elusive. Here we show that ZNF384, a member of the C2H2 family of ZnF proteins, binds DNA ends in vitro and is recruited to DSBs in vivo. ZNF384 recruitment requires the poly(ADP-ribosyl) polymerase 1 (PARP1)-dependent expansion of damaged chromatin, followed by binding of its C2H2 motifs to the exposed DNA. Moreover, ZNF384 interacts with Ku70/Ku80 via its N-terminus, thereby promoting Ku70/Ku80 assembly and the accrual of downstream cNHEJ factors, including APLF and XRCC4/LIG4, for efficient repair at DSBs. Altogether, our data suggest that ZNF384 acts as a 'Ku-adaptor' that binds damaged DNA and Ku70/Ku80 to facilitate the build-up of a cNHEJ repairosome, highlighting a role for ZNF384 in DSB repair and genome maintenance.Cancer Signaling networks and Molecular Therapeutic

Estimates of Effective Population Size and Inbreeding Level for Three Australian Pig Breeds

Selective breeding may result in higher inbreeding levels which can lead to inbreeding depression and limit future genetic gain. This study quantified inbreeding levels and evaluated effective population sizes for Large White (LW), Landrace (LR) and Duroc (DU) populations in Australia. Pedigree data from 1994 to 2015 representing about 12 generations on average were explored with the software package PopRep by Groeneveld et al. (2009) which provides multiple population parameters. Pedigree completeness was highest in 2004 and 2005 when it reached about 95% and 80% in the third and sixth generation. Average inbreeding levels were highest for these years with averages of 0.031, 0.034 and 0.050 in LW, LR and DU, respectively. Two herds joined the across-herd genetic evaluations at that time and pedigree completeness varied from 80 to 90% and from 60 to 70% in the third and sixth generation in subsequent years leading to lower estimates of inbreeding levels. Estimates of effective population size varied from 64 to 98 in LW, from 52 to 108 in LR and from 42 to 61 in DU over time. These estimates of effective population size are imprecise and an underestimate of true effective population sizes given the limited time period considered and the extent of missing pedigree