ABSTRACT
In somatic cells, H2afx and Mdc1 are close functional partners in DNA repair and damage response. However, it is not known whether they are also involved in the maintenance of genome integrity in meiosis. By analyzing chromosome dynamics in H2afx-/- spermatocytes, we found that the synapsis of autosomes and X-Y chromosomes was impaired in a fraction of cells. Such defects correlated with an abnormal recombination profile. Conversely, Mdc1 was dispensable for the synapsis of the autosomes and played only a minor role in X-Y synapsis, compared with the action of H2afx This suggested that those genes have non-overlapping functions in chromosome synapsis. However, we observed that both genes play a similar role in the assembly of MLH3 onto chromosomes, a key step in crossover formation. Moreover, we show that H2afx and Mdc1 cooperate in promoting the activation of the recombination-dependent checkpoint, a mechanism that restrains the differentiation of cells with unrepaired DSBs. This occurs by a mechanism that involves P53. Overall, our data show that, in male germ cells, H2afx and Mdc1 promote the maintenance of genome integrity.This article has an associated First Person interview with the first author of the paper.
Subject(s)
Histones/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Spermatocytes/metabolism , Adaptor Proteins, Signal Transducing , Animals , Cell Cycle Proteins , Chromosome Pairing , Genomic Instability , Genomics , Histones/genetics , Intracellular Signaling Peptides and Proteins/genetics , Male , Mice , Mice, Inbred C57BL , MutL Proteins/genetics , MutL Proteins/metabolism , Recombination, Genetic , Sex Chromosomes/genetics , Sex Chromosomes/metabolism , Spermatocytes/cytologyABSTRACT
At present,pancreatic ductal adenocarcinama (PDAC) is one of the deadliest malignant solid tumors,with poor prognosis and 5-year survival rate of 5％.Although understanding of the pathogenesis has greatly been improved for nearly two decades,there isn't a breakthrough in clinical therapy of the PDAC,and finding a new and effective therapy is badly needed.Genetic analysis showed that KRAS was one of the earliest and great probability mutated gene in the PDAC,played a significant role in initiation,progression,and metastasis of cancer,and predicted to being a good target of anti-PDAC.But a KRAS-targeted effective drug is lacking in clinic.The direct KRAS-targeted therapy will bright prospects.Meanwhile,locking localization and activity of cell membrane through post-translational modifications to KRAS combined with inhibiting KRAS downstream pathway is a good way of the KRAS-targeted PDAC therapy.
