BRCA1 and BRCA2 deficient tumor cells are sensitive to inhibitors of Poly ADP Ribose Polymerase (PARP1) through the mechanism of synthetic lethality. Several PARP inhibitors, which are oral drugs and ...generally well tolerated, have now received FDA approval for various ovarian cancer and breast cancer indications. Despite their use in the clinic, PARP inhibitor resistance is common and develops through multiple mechanisms. Broadly speaking, BRCA1/2-deficient tumor cells can become resistant to PARP inhibitors by restoring homologous recombination (HR) repair and/or by stabilizing their replication forks. Here, we review the mechanism of PARP inhibitor resistance.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
DNA double-strand breaks (DSBs) can arise from multiple sources, including exposure to ionizing radiation. The repair of DSBs involves both posttranslational modification of nucleosomes and ...concentration of DNA-repair proteins at the site of damage. Consequently, nucleosome packing and chromatin architecture surrounding the DSB may limit the ability of the DNA-damage response to access and repair the break. Here, we review early chromatin-based events that promote the formation of open, relaxed chromatin structures at DSBs and that allow the DNA-repair machinery to access the spatially confined region surrounding the DSB, thereby facilitating mammalian DSB repair.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
DNA-damaging agents are widely used in clinical oncology and exploit deficiencies in tumor DNA repair. Given the expanding role of immune checkpoint blockade as a therapeutic strategy, the ...interaction of tumor DNA damage with the immune system has recently come into focus, and it is now clear that the tumor DNA repair landscape has an important role in driving response to immune checkpoint blockade. Here, we summarize the mechanisms by which DNA damage and genomic instability have been found to shape the antitumor immune response and describe clinical efforts to use DNA repair biomarkers to guide use of immune-directed therapies.
Only a subset of patients respond to immune checkpoint blockade, and reliable predictive biomarkers of response are needed to guide therapy decisions. DNA repair deficiency is common among tumors, and emerging experimental and clinical evidence suggests that features of genomic instability are associated with response to immune-directed therapies.
Fanconi anemia (FA) is a rare genetic disorder associated with a high frequency of hematological abnormalities and congenital anomalies. Based on multilateral efforts from basic scientists and ...clinicians, significant advances in our knowledge of FA have been made in recent years. Here we review the clinical features, the diagnostic criteria, and the current and future therapies of FA and describe the current understanding of the molecular basis of the disease.
Targeting replication stress in cancer therapy da Costa, Alexandre André B A; Chowdhury, Dipanjan; Shapiro, Geoffrey I ...
Nature reviews. Drug discovery,
01/2023, Volume:
22, Issue:
1
Journal Article
Peer reviewed
Replication stress is a major cause of genomic instability and a crucial vulnerability of cancer cells. This vulnerability can be therapeutically targeted by inhibiting kinases that coordinate the ...DNA damage response with cell cycle control, including ATR, CHK1, WEE1 and MYT1 checkpoint kinases. In addition, inhibiting the DNA damage response releases DNA fragments into the cytoplasm, eliciting an innate immune response. Therefore, several ATR, CHK1, WEE1 and MYT1 inhibitors are undergoing clinical evaluation as monotherapies or in combination with chemotherapy, polyADP-ribosepolymerase (PARP) inhibitors, or immune checkpoint inhibitors to capitalize on high replication stress, overcome therapeutic resistance and promote effective antitumour immunity. Here, we review current and emerging approaches for targeting replication stress in cancer, from preclinical and biomarker development to clinical trial evaluation.
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The Fanconi anaemia pathway repairs DNA interstrand crosslinks (ICLs) in the genome. Our understanding of this complex pathway is still evolving, as new components continue to be identified and new ...biochemical systems are used to elucidate the molecular steps of repair. The Fanconi anaemia pathway uses components of other known DNA repair processes to achieve proper repair of ICLs. Moreover, Fanconi anaemia proteins have functions in genome maintenance beyond their canonical roles of repairing ICLs. Such functions include the stabilization of replication forks and the regulation of cytokinesis. Thus, Fanconi anaemia proteins are emerging as master regulators of genomic integrity that coordinate several repair processes. Here, we summarize our current understanding of the functions of the Fanconi anaemia pathway in ICL repair, together with an overview of its connections with other repair pathways and its emerging roles in genome maintenance.
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Approximately 50% of epithelial ovarian cancers (EOC) exhibit defective DNA repair via homologous recombination (HR) due to genetic and epigenetic alterations of HR pathway genes. Defective HR is an ...important therapeutic target in EOC as exemplified by the efficacy of platinum analogues in this disease, as well as the advent of PARP inhibitors, which exhibit synthetic lethality when applied to HR-deficient cells. Here, we describe the genotypic and phenotypic characteristics of HR-deficient EOCs, discuss current and emerging approaches for targeting these tumors, and present challenges associated with these approaches, focusing on development and overcoming resistance.
Defective DNA repair via HR is a pivotal vulnerability of EOC, particularly of the high-grade serous histologic subtype. Targeting defective HR offers the unique opportunity of exploiting molecular differences between tumor and normal cells, thereby inducing cancer-specific synthetic lethality; the promise and challenges of these approaches in ovarian cancer are discussed in this review.
Repair of DNA double-strand breaks (DSB) is performed by two major pathways, homology-dependent repair and classical nonhomologous end-joining. Recent studies have identified a third pathway, ...microhomology-mediated end-joining (MMEJ). MMEJ has similarities to homology-dependent repair, in that repair is initiated with end resection, leading to single-stranded 3' ends, which require microhomology upstream and downstream of the DSB. Importantly, the MMEJ pathway is commonly upregulated in cancers, especially in homologous recombination-deficient cancers, which display a distinctive mutational signature. Here, we review the molecular process of MMEJ as well as new targets and approaches exploiting the MMEJ pathway in cancer therapy.
Fanconi's anemia is a rare disorder that arises from defective repair of damaged DNA. Of the 13 Fanconi's anemia genes, 3 are breast-cancer–susceptibility genes. One is identical to
BRCA2
. Cells ...from patients with the D1 subtype of Fanconi's anemia and their family members carry biallelic mutations in
BRCA2
, and heterozygote members of kindreds with the D1 subtype have an increased risk of breast and ovarian cancer. Studies of a rare disorder can thus illuminate a common disorder.
Fanconi's anemia is a rare disorder that arises from defective repair of damaged DNA. Of the 13 Fanconi's anemia genes, 3 are breast-cancer̵1;susceptibility genes. One is identical to BRCA2. Studies of a rare disorder can illuminate a common disorder.
The study of rare genetic diseases can lead to insights into the cause and treatment of more common diseases. An example is Fanconi's anemia, a rare disorder of chromosomal instability. Studies of this disorder have elucidated the general mechanisms of bone marrow failure, cancer pathogenesis, and resistance to chemotherapy.
There are 13 genes involved in Fanconi's anemia, and 1 of them is identical to the well-known breast-cancer–susceptibility gene,
BRCA2
(Table 1). The proteins encoded by these Fanconi's anemia genes cooperate in the recognition and repair of damaged DNA. The genes are inactivated not only in Fanconi's anemia but also in . . .
BRCA1/2 proteins function in homologous recombination (HR)-mediated DNA repair and cooperate with Fanconi anemia (FA) proteins to maintain genomic integrity through replication fork stabilization. ...Loss of BRCA1/2 proteins results in DNA repair deficiency and replicative stress, leading to genomic instability and enhanced sensitivity to DNA-damaging agents. Recent studies have shown that BRCA1/2-deficient tumors upregulate Polθ-mediated alternative end-joining (alt-EJ) repair as a survival mechanism. Whether other mechanisms maintain genomic integrity upon loss of BRCA1/2 proteins is currently unknown. Here we show that BRCA1/2-deficient tumors also upregulate FANCD2 activity. FANCD2 is required for fork protection and fork restart in BRCA1/2-deficient tumors. Moreover, FANCD2 promotes Polθ recruitment at sites of damage and alt-EJ repair. Finally, loss of FANCD2 in BRCA1/2-deficient tumors enhances cell death. These results reveal a synthetic lethal relationship between FANCD2 and BRCA1/2, and they identify FANCD2 as a central player orchestrating DNA repair pathway choice at the replication fork.
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•Loss of FANCD2 and BRCA1/2 is synthetic lethal•FANCD2 maintains fork stability in BRCA1/2-deficient cells•FANCD2 promotes alternative end joining (alt-EJ)•FANCD2 overexpression confers resistance to PARP inhibitors
Kais et al. show that BRCA1/2-deficient tumors have a compensatory increase in FANCD2 activity. FANCD2 stabilizes stalled replication forks and promotes alternative end joining (alt-EJ) in BRCA1/2-deficient tumors. Loss of FANCD2 in these tumors results in severe DNA repair defects and enhanced cell death.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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