br The central role of DNA PK in
The central role of DNA-PK in the NHEJ NHEJ can be divided in several steps (Fig. 1A): 1) recognition and binding of Ku at each ends of the DSB following by the assembly of the DNA-PK at the break points and bridging; 2) phosphorylation of the DNA ends by DNA-PKcs; 3) ligation of the ends by DNA ligase IV/XRCC4 complex; 4) complex dissociation.
DNA damage repair and cancer Cancer has been described as a disease of DNA repair, pointing out the strong link between DNA repair and cancer. Studies of pre-cancerous lesions, allowed the drawing of a model for carcinogenesis. Comparison between normal cells and premalignant human tumors of urinary bladder, breast, lung and colon, have highlighted an increase of DDR activity but also an increase of the senescence and apoptosis index, early in tumorigenesis. There is indeed in these cells an increase of DSBs due to replication stress that drives genomic instability. Replication stress is generated by oncogenes and is due to checkpoint, baicalein calculator or DNA repair defects that lead to replication fork collapse and finally to DSBs. On the other hand, the high rate of senescence and apoptosis driven by the tumor suppressor p53 is a barrier to cancer. However, genomic instability in precancerous cells can lead to further mutations that confer cancer properties to cells. These mutations often affect p53 and abolish apoptosis in cancer cells but they can also affect DNA repair, cell cycle checkpoint and other apoptotic protein activities , . Sequencing of cancerous cells DNA showed an increased level of endogenous DNA damages compare to normal cells . This extensive DNA rearrangement in tumors point out the defect and abnormality of DNA damage repair in cancerous cells. Indeed, several lines of evidence show that almost all cancerous cell present DNA repair defects . Normal cells ensure DNA integrity at various cell cycle checkpoints. Cell cycle checkpoints are tightly related to DNA repair as several repair factors play the role of checkpoint proteins, or are recruited by them. Cell cycle checkpoint protein deregulations can result in a high replication rate that characterizes cancerous cells. In fact, the deleterious effect of cancerous cells comes from their capacity to cycle often. Indeed, DNA repair key factors or cell cycle checkpoint proteins defects predispose for cancer. For example deficiencies in factors that promote HR, like BRCA1 or BRCA2, predispose for breast and ovarian cancer, and mutations in the cell cycle factor ATM, increase malignancies incidences including acute leukemia . If tumors cells are deficient in one of the DNA damage repair pathway, they paradoxically strongly rely on other DNA damage repair to survive. As one of the DNA damage repair pathway is deficient in cancerous cells, they are in fact “addicted” to an alternative pathway of repair, which is often causing genetic instability. In addition, the high replication rate increase genetic instability and make them even more dependent to DNA repair . Moreover, it has been shown that an overactive DNA damage repair in cancerous cells is associated with poor prognosis for patient. An over-efficient DNA damage repair provokes resistance to DNA damaging agent and is a barrier to treatment responsivity of malignancies .
Making sense of targeting the DNA repair machinery during the course of HIV-1 infection
Acknowledgements We are grateful to Andrea Janossy for careful and critical reading of the manuscript. This work in OR and CS laboratory was supported by grants from the French agency for research on AIDS and viral hepatitis (ARNS), Sidaction, the European Union’s Horizon 2020 research and innovation program under grant agreement No 691119 — EU4HIVCURE — H2020-MSCA-RISE-2015, Alsace contre le Cancer and Institut Universitaire de France.
Introduction When confronted by a pathogen, the host’s innate immune system is activated by pattern recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs) (Brubaker et al., 2015). For viruses, the detection of viral nucleic acids is a critical element of this recognition (Luecke and Paludan, 2017, Pichlmair and Reis e Sousa, 2007). There are several intracellular DNA sensors, such as DNA-dependent activator of interferon (IFN)-regulatory factor (DAI) (Takaoka et al., 2007), absent in melanoma 2 (AIM2) (Bürckstümmer et al., 2009, Dombrowski et al., 2011, Fernandes-Alnemri et al., 2009, Hornung et al., 2009, Roberts et al., 2009), RNA polymerase III (Ablasser et al., 2009, Chiu et al., 2009), LRRFIP1 (Yang et al., 2010), DExH-box helicase (DHX)9/DHX36 (Kim et al., 2010), double-strand break repair protein MRE11 (MRE11) (Kondo et al., 2013), polyglutamine binding protein-1 (PQBP1) (Yoh et al., 2015), gamma-IFN inducible protein 16 (IFI16) (Unterholzner et al., 2010), cyclic guanosine monophosphate-AMP synthase (cGAS) (Sun et al., 2013), and DNA-dependent protein kinase (DNA-PK) (Ferguson et al., 2012, Zhang et al., 2011). However, which DNA sensors detect specific viruses, whether these PRRs act independently or cooperatively, and their relative importance in vivo require further study.