Every single cell in human body is suffering ~ 7000 DNA lesions of various types every day. Different kinds of DNA damage response (DDR) are evolved to overcome these threats to maintain genome stability. Failure in the DDR system leads to various diseases ranging from cancer to neurodevelopmental defects. Past years’ studies have unraveled the close relationship between neddylation, an ubiquitin-like modification, and DDR. This functional interplay involves the neddylation of Cullin RING E3 ligases, the prototype neddylation substrates, and non-Cullin-based neddylation targets, both of which have intimate links to DDR. More recently, unconjugated NEDD8 polymers are implicated in DDR as well. Here we summarize these findings to better understand the role that neddylation and deneddylation plays in DDR.

Chromosomal instability syndromes (CIS) show autosomal recessive inheritance patterns and are identified by breakage of the chromosome and chromosomal instability which are mostly direct results of DNA repair machinery defects that lead to many phenotypic manifestations including an increased predisposition to malignancies. The most commonly known CIS are Fanconi anaemia (FA), Nijmegen syndrome (NS), Bloom’s syndrome (BS), Ataxia-telangiectasia (A-T) and Ataxia telangiectasia like disorder (ATLD). Inherited bone marrow failure syndromes constitute a group of diseases that are extremely rare and can be described by inadequate blood cell production of single or multiple hematopoietic lineages. A major proportion of IBMFs is caused by defective genes that are involved in cellular pathways like ribosome function, telomere biology, transcription regulation, DNA repair, and telomere maintenance. In these diseases, bone marrow failure is frequently linked to other somatic abnormalities. IBMFS includes disorders such as Thrombocytopenia absent radii, Congenital amegakaryocytic thrombocytopenia and Fanconi anemia. The clinical phenotypes of these diseases are often overlapping and hence proper and accurate diagnosis is a challenge. Moreover, these diseases show great clinical heterogeneity and disease penetrance which can be explained to some extent by somatic mosaicism. Mosaicism can be a result of several mutations that have proliferated to only a small cluster of adult cells during the early developmental stages of the organism and subsequently during aging. The tissues in the body of an individual are regularly subjected to several intrinsic and extrinsic mutagenic stresses which can result in the accumulation of many genetic variations ranging from single base pair to ploidy level changes. During the past decades, somatic mosaicism has emerged as one of the major contributing factors in many monogenic disorders. These disorders are often associated with a predisposition to cancer, therefore, early and proper diagnosis is extremely important for adequate management and treatment.

As a key tumor suppressor in several cancers, BRCA1 is required for the maintenance of genomic stability. Extensive studies have revealed multiple functions of BRCA1 that contribute to its role in tumor suppression, but the most recognized one is DNA damage repair, especially DNA double-strand break (DSB) repair. Once recruited to DSB in S/G2 phase of the cell cycle, BRCA1 promotes DSB repair through homologous recombination (HR). Mechanistically, it is well known that BRCA1 is required for the efficient loading of RAD51 recombinase to DSB. Studies in the past decade reveal that BRCA1 also regulates DNA end resection to generate single-stranded DNA (ssDNA) required for RAD51 loading and promotes RAD51-mediated synaptic complex assembly. In this review, we will summarize the underlying mechanisms of the recruitment BRCA1 to DSB and BRCA1’s functions at multiple stages of HR in DSB repair. We will also discuss how HR defects caused by BRCA1 deficiency can be rescued by modulating DSB repair pathway choice.

Fanconi Anemia (FA) is a rare inherited hematological disease, caused by mutations in genes involved in the DNA interstrand crosslink (ICL) repair. Up to date, 22 genes have been identified that encode a series of functionally associated proteins that recognize ICL lesion and mediate the activation of the downstream DNA repair pathway including nucleotide excision repair, translesion synthesis, and homologous recombination. The FA pathway is strictly regulated by complex mechanisms such as ubiquitination, phosphorylation, and degradation signals that are essential for the maintenance of genome stability. Here, we summarize the discovery history and recent advances of the FA genes, and further discuss the role of FA pathway in carcinogenesis and cancer therapies.

CLASPIN is an essential mediator of ATR-dependent CHK1 activation in the DNA replication checkpoint. K6-linked polyubiquitination of CLASPIN promotes its chromatin loading and subsequent CHK1 activation. Here, we found that ubiquitin-specific protease 11 (USP11) deubiquitinates the K6-linkage polyubiquitinated form of CLASPIN. Under steady-state conditions, USP11 interacts with CLASPIN, reducing CLASPIN K6-linked ubiquitination levels. In response to replication stress, USP11 is phosphorylated by ATR and subsequently disassociated from CLASPIN, promoting CLASPIN chromatin loading, CHK1 activation and ultimately genome stability. Taken together, our findings uncover a novel function of USP11 in negatively regulating CHK1 activation by suppressing CLASPIN chromatin loading.