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Irradiation-induced damage and the DNA damage response
Published in Michael C. Joiner, Albert J. van der Kogel, Basic Clinical Radiobiology, 2018
Conchita Vens, Marianne Koritzinsky, Bradly G. Wouters
A number of proteins help decide whether to engage the NHEJ or HR process in repairing a DSB. CDK1 activity regulates DNA end resection required for HR, thereby preventing cells from attempting HR in G1. Furthermore, phosphorylation of H2AX promotes ubiquitylation of H2A proteins by RNF8 and RNF168 in the surrounding chromatin, which serves as a signalling platform for the attraction of pathway-specific repair factors. Mono-ubiquitylated H2A attracts the protein 53BP1 which directs repair towards NHEJ in G1 by mediating end resection at DNA breaks that directly antagonize HR factors (25). Poly-ubiquitination chains on the chromatin conversely attract the adaptor protein RAP80 which recruits the HR protein machinery (5).
Patented therapeutic approaches targeting LRP/LR for cancer treatment
Published in Expert Opinion on Therapeutic Patents, 2019
Leila Vania, Gavin Morris, Tyrone C Otgaar, Monique J Bignoux, Martin Bernert, Jessica Burns, Anne Gabathuse, Elvira Singh, Eloise Ferreira, Stefan F T Weiss
As mentioned above, targeting proteins involved in enhancing LRP/LR’s tumourigenic function may be a potential therapy against cancer. It is known that LRP/LR has several roles within the nucleus including maintaining nuclear structures. The receptor is also found to play a role in importing and anchoring the E3 protein-ubiquitin ligase RNF8, to nucleosomes in the nucleolus [177]. Studies have shown that RNF8 plays a central role in the DNA damage response to double stranded breaks (DSBs) [110]. In the absence of DNA damage, RNF8 is localized to the nucleosome. In the event of DNA damage, the DNA-damage repair enzyme BRCA1 (breast cancer susceptibility protein 1) translocates to nucleosomes bound by RNF8, which is stabilized by LRP/LR [177] (Figure 7). During the DNA damage response, RNF8 and BRCA1 are then released into the nucleoplasm where they coordinate DSB DNA damage response (DDR). Therefore, disrupting the interaction between LRP/LR and RNF8 in the cytosol, may result in an impaired DNA repair response in tumorigenic cells. Consequently, this may lead to DNA-damage induced cell-cycle arrest and apoptosis, ultimately aiding as a therapeutic approach for the treatment of cancer.
The relationship between histone posttranslational modification and DNA damage signaling and repair
Published in International Journal of Radiation Biology, 2019
Ajit K Sharma, Michael J. Hendzel
Ubiquitylation plays a key role in the recruitment of DDR factors that are involved in enhancing DDR activation. The RNF8 E3 ubiquitin ligase is upstream in a pathway that is ultimately responsible for regulating the assembly of 53BP1 and the BRCA1-A complex at sites of DSBs. The initial reports provided evidence that this occurred through the UBC13-dependent assembly of K63-linked polyubiquitin chains on histone H2A (Feng and Chen 2012). Interestingly, it was reported that histone H1 is the target for the assembly of K63-linked ubiquitin chains (Thorslund et al. 2015). RNF8 will first ubiquitylate H1, leading to the recruitment of RNF168, which, in turn, monoubiquitinates H2A at lysine 13/15 in human cells. RNF168 can bind its own product, which will lead to increasing concentrations of RNF168 at the break site and further amplification of H2A monoubiquitylation (Doil et al. 2009; Stewart et al. 2009; Mattiroli et al. 2012). One limitation of H1 as the substrate is that H1 is normally very transiently associated with chromatin (Lever et al. 2000; Misteli et al. 2000). This would suggest that H1 must be rapidly deubiquitylated in order to prevent the spreading of the K63-linked polyubiquitin chains to other regions of chromatin that are not damaged.