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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).
The Premature Aging Characteristics of RecQ Helicases
Published in Shamim I. Ahmad, Aging: Exploring a Complex Phenomenon, 2017
Christ Ordookhanian, Taylor N. Dennis, J. Jefferson P. Perry
RecQ4 has been implicated in having functions across many of the DNA repair pathways, with RTS cells or cells with RecQ4 knockdown observed to fail to start DNA synthesis after UV irradiation or hydroxyurea treatment [158,159]. RecQ4 has also been indicated to directly interact with the DNA damage sensor PARP-1, where PARP-1 was observed to PARylate the C-terminus of RECQL4 [129]. The range of sensitivities to DNA damaging agents varies, with RTS fibroblasts having hypersensitivity to hydroxyurea, camptothecin, and doxorubicin [36], they have mild sensitivity to UV light, ionizing radiation, or cisplatin [21], and have limited sensitivity to NER-related 4-nitroquinolone oxide damage (4-NQO) [36]. RecQ4 functions in repair of DNA DSBs were initially supported due to RecQ4 co-immunoprecipitating with HRR protein RAD51. More recently, functions for RecQ4 have been observed in DNA-end resection, which is an initial and essential step of HRR [160]. RecQ4 depletion was observed to dramatically reduce cellular 5′-end resection and HRR rates. RecQ4 was further shown to physically interact with the MRE11–RAD50–NBS1 (MRN) complex that functions to initiate DNA-end resection. The N-terminus of RecQ4 was determined to bind to the MRN partner CtIP, which functions with the MRN complex to sense DSBs and to initiate DNA-end resection, while the RecQ4 helicase activity was shown to be critical for promoting DNA-end processing and efficient HRR. RecQ4 may also have functions in the restart of replication forks, as RTS cells are sensitive to agents that interfere with replication [142]. Potential NHEJ functions are indicated by RecQ4 co-immunoprecipitating with KU70/80, and that depletion of RecQ4 was also observed to reduce cellular NHEJ activity.
Emerging predictive biomarkers in the management of bone and soft tissue sarcomas
Published in Expert Review of Anticancer Therapy, 2023
Candace L. Haddox, Richard F. Riedel
Comprehensive molecular profiling of sarcomas revealed that several subtypes have alterations within homologous recombination DNA repair (HRR) genes, which may be exploited by inhibitors of DNA damage repair [23,44,48]. Normal cells have evolved several sophisticated mechanisms for ensuring accurate repair of DNA damage [49]. Beyond a critical threshold of DNA damage, cells enter a senescent state or undergo apoptosis. Double-stranded DNA breaks (DSBs) are particularly lethal and are often repaired by HRR, wherein a homologous sister chromatid is used as a template strand for high-fidelity repair. HRR involves a complex cascade of molecular events wherein ATM and ATR kinases activate several key effector proteins, DNA end resection is performed by nucleases, and interactions between BRCA1, BRCA2, and PALB2 result in loading of the DNA recombinase RAD51 to sites of DNA damage. RAD51 loading and formation of nucleoprotein filaments allows the damaged strand to invade the intact homologous strand, and DNA synthesis occurs.
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
As cells progress from G1 to S-phase, cells begin to utilize the error-free homologous recombination repair pathway and suppress non-homologous end-joining pathway. Histone modifications play an important role in this selection process by regulating the binding of 53BP1, which, when retained at DSBs, inhibits DNA end resection and, consequently, homologous recombination repair. 53BP1 binds to sites of DNA damage by interacting with specific histone modifications. 53BP1 binds to methylated lysine 20 on histone H4 and to ubiquitylated lysine 15 on histone H2A (Fradet-Turcotte et al. 2013). The methylation of histone H4 is constitutive (Pesavento et al. 2008) while the ubiquitylation is induced upon DNA damage (Lilley et al. 2010). The switch away from 53BP1 is facilitated by dilution of histone H4 methylation during replication (Pellegrino et al. 2017). Directed regulation can further be mediated by both the NuA4/Tip60 acetyltransferase and MOF acetyltransferase (Tang et al. 2013; Jacquet et al. 2016; Li et al. 2010). MOF inhibits 53BP1 binding through acetylation of histone H4 on lysine 16 (Li et al. 2010), which precludes 53BP1 binding through methylated histone H4 lysine 20 (Tang et al. 2013). While knockdown of NuA4 correlates with a loss of histone H4 acetylation, MOF is established as the lysine 16 acetyltransferase (Taipale et al. 2005) and identification of NuA4/Tip60 as an H2AK15 acetyltransferase active at sites of DNA damage (Jacquet et al. 2016) provides an explanation for how Tip60 inhibits 53BP1 binding. Tip60 acetylates and thereby excludes the DNA damage-inducible RNF168-mediated ubiquitylation of histone H2A on lysine 15. Consequently, an interplay between histone acetylation and ubiquitylation signaling play major regulatory roles in determining repair pathway utilization and the cell cycle dependence of HR repair and is summarized in Figure 2.
PARP inhibitors as single agents and in combination therapy: the most promising treatment strategies in clinical trials for BRCA-mutant ovarian and triple-negative breast cancers
Published in Expert Opinion on Investigational Drugs, 2022
Another class of proteins that regulate DNA repair pathways are the CDKs [105]. Previous studies reported that when DSB occurs, 53BP1 and RIF1 proteins inhibit BRCA1 recruitment to the DSB lesions, leading to the inhibition of DNA end resection and promoting the activation of the NHEJ repair pathway [106]. DNA end resection, which generates a long 3′ single-stranded DNA (ssDNA) tail that can invade the homologous DNA strand [107], is a vital step in HR repair and is dependent on the kinase activities of at least two CDKs (CDK5 and CDK12). Both these CDKs participate in the PARPi resistance [108]. For example, when CDK5 is knocked out in HeLa cells, these cells become more sensitive to PARPi [108]. Furthermore, the analysis of genome-wide profiling of synthetic genetic lethality in HGSOC also identified CDK12 as a novel marker of PARP1/2 sensitivity [109]. Consistently, knockout of CDK12 disrupts HR repair and sensitizes ovarian cancer cells to cisplatin and PARPi [110]. CDK12 inhibition can also reverse intrinsic or required PARPi resistance in TNBC cells, and patient-derived xenograft (PDX) models derived from TNBC patients [111]. Other studies have reported that other CDKs with regulatory activities it the G1 to S transition (CDK2, 4, and 6) may also be involved in modulating PARPi. For example, a recent study suggests that CDK4/6 inhibitor (palbociclib) combined with PARPi was synergistic in mediating a therapeutic response as compared to single agents in treating BRCA-mutant ER (+) breast cancer cells [112]. Additionally, CDK2 combined with PARPi display synergistic effects in BRCA1-mutant breast cancer due to the identification of convergence between BRCA1 loss and high cyclin E1 expression using a basal-like breast cancer cohort [113]. Intriguingly, when the CDKs inhibitor dinaciclib is combined with PARPi (niraparib) it can resensitize niraparib-resistant TNBC cells through downregulating MYC expression and inhibiting HR, EMT, and cancer stem-like phenotype [114]. This synthetic lethal strategy can further expand in effectively treating ovarian, prostate, colon, and lung cancer cells independent of BRCA status [114]. The only early-phase clinical trial currently investigates the combination treatment of veliparib and the CDK inhibitor dinaciclib in advanced solid tumors (NCT01434316) (Table 4).