BRCA1 mutation spectrum, functions, and therapeutic strategies: The story so far

Sharma, Babita; Kaur, Raman Preet; Raut, Sonali; Munshi, Anjana

doi:10.1016/j.currproblcancer.2018.01.001

Cited by 22 publications

(21 citation statements)

References 191 publications

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“…In DSBs repair by HR, BRCA1 participates as a central component of macromolecular protein complexes, each one composed of unique protein binding partners, as phosphorylated ABRAXAS, BACH1 and CtIP [ 8 , 28 , 56 , 57 ] ( Figure 4 ). These complexes, called BRCA1 A, B, C and D helped to recognize the multiple functions of BRCA1 not only in DDR, but also in the transcriptional regulation of genes involved in other cellular processes [ 56 , 58 ]. Interestingly, in all complexes, BRCA1 exists as a heterodimer with BARD1 ( Figure 4 ), with distinct and sometimes overlapping roles for maintenance of genomic stability [ 56 ].…”

Section: Role Of Brca1 In Dsbs Repairmentioning

confidence: 99%

Exploiting DNA Damage Repair in Precision Cancer Therapy: BRCA1 as a Prime Therapeutic Target

Raimundo

Calheiros

2021

Cancers

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Precision medicine aims to identify specific molecular alterations, such as driver mutations, allowing tailored and effective anticancer therapies. Poly(ADP)-ribose polymerase inhibitors (PARPi) are the prototypical example of targeted therapy, exploiting the inability of cancer cells to repair DNA damage. Following the concept of synthetic lethality, PARPi have gained great relevance, particularly in BRCA1 dysfunctional cancer cells. In fact, BRCA1 mutations culminate in DNA repair defects that can render cancer cells more vulnerable to therapy. However, the efficacy of these drugs has been greatly affected by the occurrence of resistance due to multi-connected DNA repair pathways that may compensate for each other. Hence, the search for additional effective agents targeting DNA damage repair (DDR) is of crucial importance. In this context, BRCA1 has assumed a central role in developing drugs aimed at inhibiting DNA repair activity. Collectively, this review provides an in-depth understanding of the biology and regulatory mechanisms of DDR pathways, highlighting the potential of DDR-associated molecules, particularly BRCA1 and its interconnected partners, in precision cancer medicine. It also affords an overview about what we have achieved and a reflection on how much remains to be done in this field, further addressing encouraging clues for the advance of DDR targeted therapy.

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Section: Role Of Brca1 In Dsbs Repairmentioning

confidence: 99%

Exploiting DNA Damage Repair in Precision Cancer Therapy: BRCA1 as a Prime Therapeutic Target

Raimundo

Calheiros

2021

Cancers

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“…Germline mutations in the TS gene BRCA1 account for 25-30% of hereditary breast-and ovarian cancer. It plays a major role in homologous recombination and other DNA repair mechanisms [25].…”

Section: Selection Of Genes For An Epimutation Screenmentioning

confidence: 99%

Hypermethylation of RAD9A intron 2 in childhood cancer patients and tumor cell lines

Galetzka

Bock²,

Dittrich

et al. 2019

Preprint

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Background Most childhood cancers occur sporadically and cannot be explained by an inherited mutation or unhealthy lifestyle. The prenatal origins hypothesis postulates a role for (epi)genetic mutations which occur stochastically in rapidly dividing cells. This study aims to investigate the impact of adverse methylation in tumor relevant genes in former childhood cancer patients which may be associated with an enhanced risk to develop primary secondary cancers Methods We performed an epimutation screen of several candidate genes (APC, CDKN2A, EFNA5, RAD9A, and TP53), in skin fibroblasts of 20 patients with a primary cancer in childhood and subsequent second primary cancer (2N), 20 matched patients with only one primary cancer in childhood (1N), 20 cancer free controls (0N) and unrelated leukemia cancer samples, using bisulfite pyrosequencing and deep bisulfite sequencing. radiation, colony formation assays, cell proliferation, PCR and molecular karyotype SNP-array, experiments were performed to further characterize RAD9A hypermethylation in fibroblasts and FaDu sub clones. Data were analyzed using the Kruskal-Wallis rank sum test and Benjamini-Hochberg procedure, the linear mixed-effects model was fit using REML and R-scripts. Results Four 1N patients and one 2N patient displayed elevated (10%) mean methylation levels of RAD9A intron 2. Deep bisulfite sequencing of RAD9A in these patients revealed 2% allele methylation errors (defined as alleles with >60% methylated CpGs). We found RAD9A hypermethylation in bone marrow of patients with pre-ALL (pre-acute lymphoblastic leukaemia), AML (acute myloid leukaemia), and plasmablastic lymphoma (PBL), and in EBV-(Epstein Barr virus) transformed lymphoblastoid cells. RAD9A methylation in fibroblasts or tumor cells (FaDu) was not affected by in vitro aging, or DNA damage induced by radiation or the chemotherapeutical daunorubicin. Molecular karyotyping of FaDu sub clones revealed a homozygous inactivation of CHD2, SPATA8 and SMARCA1, in clones with hypermethylation in RAD9A. Conclusion We propose that constitutive RAD9A epimutations may have arisen early in development, predisposing the compromised cells to tumorigenesis and increased childhood cancer risk. Analyses of tumor cell clones with high methylation levels of RAD9A suggest a connection between methylation levels of the RAD9A intron 2 locus and a homozygous inactivation of important genes

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“…BRCA1/BARD1 mediates the polyubiquitination via Lys6 of ubiquitin, which acts as a post-translational modification [ 29 – 31 ]. Ubiquitinated BRCA1/BARD1 substrates, including RBBP8 and NMP1, have been implicated in the assembly of protein complexes important for homologous recombination [ 32 , 33 ]. BRCA1/BARD1 itself is a substrate for its own ubiquitin ligase E3 activity, which increases the stability and activity of the complex [ 30 , 34 ].…”

Section: Brca1 Structure and Functionmentioning

confidence: 99%

A new bioinformatics tool to help assess the significance of BRCA1 variants

et al. 2018

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BackgroundGermline pathogenic variants in the breast cancer type 1 susceptibility gene BRCA1 are associated with a 60% lifetime risk for breast and ovarian cancer. This overall risk estimate is for all BRCA1 variants; obviously, not all variants confer the same risk of developing a disease. In cancer patients, loss of BRCA1 function in tumor tissue has been associated with an increased sensitivity to platinum agents and to poly-(ADP-ribose) polymerase (PARP) inhibitors. For clinical management of both at-risk individuals and cancer patients, it would be important that each identified genetic variant be associated with clinical significance. Unfortunately for the vast majority of variants, the clinical impact is unknown. The availability of results from studies assessing the impact of variants on protein function may provide insight of crucial importance.Results and conclusionWe have collected, curated, and structured the molecular and cellular phenotypic impact of 3654 distinct BRCA1 variants. The data was modeled in triple format, using the variant as a subject, the studied function as the object, and a predicate describing the relation between the two. Each annotation is supported by a fully traceable evidence. The data was captured using standard ontologies to ensure consistency, and enhance searchability and interoperability. We have assessed the extent to which functional defects at the molecular and cellular levels correlate with the clinical interpretation of variants by ClinVar submitters. Approximately 30% of the ClinVar BRCA1 missense variants have some molecular or cellular assay available in the literature. Pathogenic variants (as assigned by ClinVar) have at least some significant functional defect in 94% of testable cases. For benign variants, 77% of ClinVar benign variants, for which neXtProt Cancer variant portal has data, shows either no or mild experimental functional defects. While this does not provide evidence for clinical interpretation of variants, it may provide some guidance for variants of unknown significance, in the absence of more reliable data.The neXtProt Cancer variant portal (https://www.nextprot.org/portals/breast-cancer) contains over 6300 observations at the molecular and/or cellular level for BRCA1 variants.

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BRCA1 mutation spectrum, functions, and therapeutic strategies: The story so far

Cited by 22 publications

References 191 publications

Exploiting DNA Damage Repair in Precision Cancer Therapy: BRCA1 as a Prime Therapeutic Target

Exploiting DNA Damage Repair in Precision Cancer Therapy: BRCA1 as a Prime Therapeutic Target

Hypermethylation of RAD9A intron 2 in childhood cancer patients and tumor cell lines

A new bioinformatics tool to help assess the significance of BRCA1 variants

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