High-risk human papillomaviruses (HPV) cause 5% of all human cancers and are primary etiologic agents of cervical, anal, and oropharyngeal cancer. HPV infection is necessary, but not sufficient per se to produce cancer: additional changes must occur that transform HPV-infected cells to malignancy. The HPV oncoproteins E6 and E7 immortalize human keratinocytes, cervical cells, and fibroblasts in culture. Each oncoprotein interacts with a variety of cellular binding partners; most important for transformation are E6 and E7’s interactions with p53 and RB (respectively) which lead to degradation of p53 and RB through the ubiquitin pathway. Inactivation of p53 and RB leads to inactivation of pivotal cell cycle checkpoints, thereby stimulating cell proliferation and allowing cell division to occur independently of the presence of DNA damage, replicative stress, and other such insults, leading to genome instability. Continuous expression of E6/E7 drives the proliferation and progression of most HPV-mediated cancers of the cervix and a substantial fraction of those of the oropharynx. However, at both cancer sites, “HPV-inactive” tumors that contain HPV DNA, but do not express E6/E7 arise. We propose that these HPV-inactive cancers begin as HPV-driven lesions, but lose E6/E7 expression at some point during progression. We have recently shown that p53 deletion in HPV-immortalized, premalignant cells allows for the emergence of cell populations that no longer express E6/E7. These findings corroborate the notion of a pivotal role of p53 in the context of HPV-mediated transformation, both at the initiation and progression stages of cancer development.

DNA replication is one of the most critical psychological process, which mainly consists of three steps: initiation, elongation, and termination. Precise regulation through all stages of DNA replication is essential for maintaining genome integrity in proliferating cells. During each cell cycle, the complete genetic information existing in the DNA needs to be duplicated and passed on to the daughter cells. The DNA replication machinery is confronted with many challenges and stresses owing to endogenous and exogenous facts that could harm the faithful duplication of the DNA. The abnormality of DNA replication could cause genomic instability and tumorigenesis. ATR is a master regulator of cells in response to DNA replication stress to safeguard genomic stability and prevent tumorigenesis. In the past years, the key functions of post-translational modification (PTM) in ATR signaling transduction has been explored. ATR signaling is complicatedly and tightly regulated by multiple PTMs, such as phosphorylation, acetylation, ubiquitination, SUMOylation and so on. Here, we summarize how the ATR signaling pathway is tightly regulated by PTM. Furthermore, we describe the critical roles of ATR signaling in DNA replication and safeguarding genomic stability. In the past years, the key functions of post-translational modification (PTM) in DNA replication has been explored. These findings benefit for us better understand the complicated mechanism of DNA replication signaling pathway.

The nuclear envelope (NE) not only shields the genetic material inside the nucleus, maintains the dynamic shapes of nucleus, and regulates nuclear exchange with cytosol, but also participates in DNA replication, damage repair and transcription regulation. The loss of NE integrity, as observed in various diseases, has been shown to cause genome instability as a result of genetic material leaking into the cytoplasm. An underestimated but critically important factor of genome integrity is the role of NE components that involve in DNA replication and damage repair. In this review, we summarize the triggers of NE loss and its cellular consequences by focusing on the interactions between NE components and DNA replication and repair factors. Studies on how NE mediates DNA replication and damage repair could shed light on the diagnosis and treatment of human diseases such as cancer and laminopathy.

The adaptive immune system can diversify the antigen receptors to eliminate various pathogens through programmed DNA lesions at antigen receptor genes. In immune diversification, general DNA repair machineries are applied to transform the programmed DNA lesions into gene mutation or recombination events with common and unique features. Here we focus on antibody class switch recombination (CSR), and review the initiation of base damages, the conversion of damaged base to DNA double-strand break, and the ligation of broken ends. With an emphasis on the unique features in CSR, we discuss recent advances in the understanding of DNA repair/replication coordination, and ERCC6L2-mediated deletional recombination. We further elaborate the application of CSR in end-joining, resection and translesion synthesis assays. In the time of the COVID-19 pandemic, we hope it help to understand the generation of therapeutic antibodies.

SIRT7 plays critical roles in tumorigenesis and tumor progression; however, the underlying mechanisms are poorly understood. Here, we aimed to identify downstream targets of SIRT7 to help delineate its precise function. In this study, we demonstrate that SIRT7 is essential to regulate IDH1 expression in various cancer cell types. Interestingly, both SIRT7 and IDH1 levels are downregulated in breast cancer lung metastases and are useful for predicting disease progression and prognosis. Mechanistically, SIRT7 enhances IDH1 transcription, and this process is mediated by SREBP1. SIRT7 insufficiency reduces cellular α-ketoglutarate, a metabolite product of IDH1, and suppresses lipogenesis and gluconeogenesis. Moreover, α-ketoglutarate decline increases HIF1α protein levels and, thus, promotes glycolysis. This effect permits cancer cells to facilitate Warburg effect and undergo fast proliferation. Overall, the SIRT7–IDH1 axis regulates cancer cell metabolic reprogramming and, thus, might serve as a point of therapeutic intervention.