Unsolved mystery: the role of BRCA1 in DNA end-joining

Saha, Janapriya; Davis, Anthony J.

doi:10.1093/jrr/rrw032

Cited by 31 publications

(22 citation statements)

References 55 publications

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“…Piccirilli et al [24] described a series of 11 patients with a history of invasive breast carcinoma who subsequently developed GBM; however, an analysis of BRCA1 or BRCA2 mutational status was not performed. BRCA1 defects are known to dysregulate cell checkpoint pathways and impair the fidelity of the DNA damage response, particularly to double-strand breaks (DSBs) [25]. We speculate that GBM cells with BRCA1 defects might exhibit particularly high levels of genomic instability when exposed to DSB-inducing agents such as RT and temozolomide, increasing the risk of treatment-induced cancer evolution and acquiring new, aggressive phenotypes.…”

Section: Discussionmentioning

confidence: 99%

Widely metastatic glioblastoma with BRCA1 and ARID1A mutations: a case report

et al. 2020

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Background: Glioblastoma (GBM) is a highly malignant brain neoplasm with poor survival. Despite its aggressive nature, metastatic spread of GBM is identified only rarely. While the molecular alterations associated with GBM and its subtypes are well-described, there remains a gap in understanding which alterations may predispose towards metastasis. In this report, we present a case of GBM with multi-organ metastases and discuss its genomic alterations. Case presentation: A 74-year-old woman was diagnosed with left occipital glioblastoma (IDH-wildtype, MGMTunmethylated), for which she underwent resection, standard chemoradiation, and then stereotactic radiosurgery (SRS) for local recurrence. One month after SRS, work-up for a pathologic hip fracture revealed a left breast mass, lytic lesions involving pelvic bones, and multiple pulmonary and hepatic lesions. Biopsies of the breast and bone lesions both demonstrated metastatic IDH-wildtype GBM. For worsening neurologic symptoms, the patient underwent debulking of a large right temporal lobe recurrence and expired shortly thereafter. Autopsy confirmed metastatic GBM in multiple systemic sites, including bilateral lungs, heart, liver, thyroid, left breast, small bowel, omentum, peritoneal surfaces, visceral surfaces, left pelvic bone, and hilar lymph nodes. Targeted sequencing was performed on tissue samples obtained pre-and postmortem, as well as on cell cultures and an orthotopic mouse xenograft derived from premortem surgical specimens. A BRCA1 mutation (p.I571T) was the only variant found in common among the primary, recurrence, and metastatic specimens, suggesting its likely status as an early driver mutation. Multiple subclonal ARID1A mutations, which promote genomic instability through impairment of DNA mismatch repair, were identified only in the recurrence. Mutational spectrum analysis demonstrated a high percentage of C:G to T:A transitions in the post-treatment samples but not in the primary tumor. Conclusion: This case report examines a rare case of widely metastatic IDH-wildtype GBM with a clonal somatic mutation in BRCA1. Post-treatment recurrent tumor in the brain and in multiple systemic organs exhibited evidence of acquired DNA mismatch repair deficiency, which may be explained by functional loss of ARID1A. We identify a potential role for immune checkpoint and PARP inhibitors in the treatment of metastatic GBM.

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Section: Discussionmentioning

confidence: 99%

Widely metastatic glioblastoma with BRCA1 and ARID1A mutations: a case report

et al. 2020

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“…p53 can either promote cell cycle arrest at G1 phase and NHEJ, or apoptosis if damage are too serious or if cells are in S/G2 phase [24]. The precise function of BRCA1 is still unclear but it could block DNA-PKcs auto-phosphorylation and promotes HR in S/G2 phase [25].…”

Section: Regulators Of Nhej: the Repair Pathway Choicementioning

confidence: 99%

Targeting the DNA-PK complex: Its rationale use in cancer and HIV-1 infection

Schwartz

Rohr

Wallet

2019

Biochemical Pharmacology

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“…In cancer cells, functions of BRCA1 are most established in homologous recombination, which can only be seen in dividing cells [5,6]. However, BRCA1 has also been reported to be involved in non-homologous end-joining [28] and transcription-associated homologous recombination repair [29,30], which also occur in non-dividing cells, including mature neurons [31][32][33]. Since DNA damage in neurons has been reported in various neurodegenerative diseases [34,35], including PiD [36,37] and PSP [37], the mislocalization and coaggregation of BRCA1 with tau suggested in PiD and PSP in this study may also be involved in the progression of these diseases.…”

Section: Discussionmentioning

confidence: 99%

Colocalization of BRCA1 with Tau Aggregates in Human Tauopathies

et al. 2019

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The mechanism of neuronal dysfunction via tau aggregation in tauopathy patients is controversial. In Alzheimer’s disease (AD), we previously reported mislocalization of the DNA repair nuclear protein BRCA1, its coaggregation with tau, and the possible importance of the subsequent DNA repair dysfunction. However, whether this dysfunction in BRCA1 also occurs in other tauopathies is unknown. The aim of this study was to evaluate whether BRCA1 colocalizes with tau aggregates in the cytoplasm in the brains of the patients with tauopathy. We evaluated four AD, two Pick’s disease (PiD), three progressive supranuclear palsy (PSP), three corticobasal degeneration (CBD), four normal control, and four disease control autopsy brains. Immunohistochemistry was performed using antibodies against BRCA1 and phosphorylated tau (AT8). Colocalization was confirmed by immunofluorescence double staining. Colocalization of BRCA1 with tau aggregates was observed in neurofibrillary tangles and neuropil threads in AD, pick bodies in PiD, and globose neurofibrillary tangles and glial coiled bodies in PSP. However, only partial colocalization was observed in tuft-shaped astrocytes in PSP, and no colocalization was observed in CBD. Mislocalization of BRCA1 was not observed in disease controls. BRCA1 was mislocalized to the cytoplasm and colocalized with tau aggregates in not only AD but also in PiD and PSP. Mislocalization of BRCA1 by tau aggregates may be involved in the pathogenesis of PiD and PSP.

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Unsolved mystery: the role of BRCA1 in DNA end-joining

Cited by 31 publications

References 55 publications

Widely metastatic glioblastoma with BRCA1 and ARID1A mutations: a case report

Widely metastatic glioblastoma with BRCA1 and ARID1A mutations: a case report

Targeting the DNA-PK complex: Its rationale use in cancer and HIV-1 infection

Colocalization of BRCA1 with Tau Aggregates in Human Tauopathies

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