The kinesin KIF18B interacts with 53BP1 and is required for efficient double strand break repair
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Genetic changes can lead to detrimental genomic instability, mutagenesis, oncogenesis and premature aging. The DNA damage response (DDR) is responsible for safeguarding the genome from such harmful alterations. 53BP1 (p53 binding protein 1) is a key mediator in the DDR (DNA damage response). 53BP1 influences the critical decision of whether to utilise NHEJ (non-homologous end joining) rather than HR (homologous recombination), and facilitates distal NHEJ, binding chromatin in the vicinity of damage and mobilising the DSB (double strand break). We identified a novel 53BP1 interactor and DDR component, the kinesin KIF18B. KIF18B is required for efficient DSB repair and proper recruitment of 53BP1 to DSBs. This molecular motor protein is chromatin bound and interacts with the nucleosome and 53BP1 through its C-terminal region. Notably, the motor domain of KIF18B is required for efficient 53BP1 focal recruitment in response to damage induced by ionising radiation. Our observations suggest that KIF18B is involved in distal NHEJ in association with 53BP1, potentially using its motor function to assist in the movement of DSBs. We also attempted to generate a DT40 chicken cell line with a minimal complement of histone genes. This genetic tool would allow the functional examination of specific histone residues and their post-translational modifications. Histones are vital in chromatin regulation; modification of their residues is necessary for appropriate signalling in biological processes, including the DNA damage response. We found that chicken DT40 cells could compensate for the loss of one allele of their major histone cluster. However, our attempt to minimise the locus to just three copies of each histone gene was unsuccessful. Our observations suggest that the tightly regulated system was unable to cope with the imbalance of histones at various stages of gene targeting and that cells adapted to avoid this genetic manipulation.
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