Leveraging the replication stress response to optimize cancer therapy

E Cybulla, A Vindigni - Nature Reviews Cancer, 2023 - nature.com
High-fidelity DNA replication is critical for the faithful transmission of genetic information to
daughter cells. Following genotoxic stress, specialized DNA damage tolerance pathways …

BRCAness, DNA gaps, and gain and loss of PARP inhibitor–induced synthetic lethality

X Li, L Zou - The Journal of clinical investigation, 2024 - jci.org
Mutations in the tumor-suppressor genes BRCA1 and BRCA2 resulting in BRCA1/2
deficiency are frequently identified in breast, ovarian, prostate, pancreatic, and other …

Replication gaps are a key determinant of PARP inhibitor synthetic lethality with BRCA deficiency

K Cong, M Peng, AN Kousholt, WTC Lee, S Lee… - Molecular cell, 2021 - cell.com
Mutations in BRCA1 or BRCA2 (BRCA) is synthetic lethal with poly (ADP-ribose)
polymerase inhibitors (PARPi). Lethality is thought to derive from DNA double-stranded …

[HTML][HTML] Exploiting replication gaps for cancer therapy

K Cong, SB Cantor - Molecular cell, 2022 - cell.com
Defects in DNA double-strand break repair are thought to render BRCA1 or BRCA2 (BRCA)
mutant tumors selectively sensitive to PARP inhibitors (PARPis). Challenging this …

[HTML][HTML] POLθ processes ssDNA gaps and promotes replication fork progression in BRCA1-deficient cells

A Schrempf, S Bernardo, EAA Verge, MAR Otero… - Cell reports, 2022 - cell.com
Polymerase theta (POLθ) is an error-prone DNA polymerase whose loss is synthetically
lethal in cancer cells bearing breast cancer susceptibility proteins 1 and 2 (BRCA1/2) …

EXO1 protects BRCA1-deficient cells against toxic DNA lesions

B van de Kooij, A Schreuder, R Pavani, V Garzero… - Molecular Cell, 2024 - cell.com
Inactivating mutations in the BRCA1 and BRCA2 genes impair DNA double-strand break
(DSB) repair by homologous recombination (HR), leading to chromosomal instability and …

Roles of trans-lesion synthesis (TLS) DNA polymerases in tumorigenesis and cancer therapy

J Anand, L Chiou, C Sciandra, X Zhang, J Hong… - NAR …, 2023 - academic.oup.com
DNA damage tolerance and mutagenesis are hallmarks and enabling characteristics of
neoplastic cells that drive tumorigenesis and allow cancer cells to resist therapy. The 'Y …

ATR protects ongoing and newly assembled DNA replication forks through distinct mechanisms

W Leung, A Simoneau, S Saxena, J Jackson, PS Patel… - Cell reports, 2023 - cell.com
The ATR kinase safeguards genomic integrity during S phase, but how ATR protects DNA
replication forks remains incompletely understood. Here, we combine four distinct assays to …

Multi-step processing of replication stress-derived nascent strand DNA gaps by MRE11 and EXO1 nucleases

A Hale, A Dhoonmoon, J Straka, CM Nicolae… - Nature …, 2023 - nature.com
Accumulation of single stranded DNA (ssDNA) gaps in the nascent strand during DNA
replication has been associated with cytotoxicity and hypersensitivity to genotoxic stress …

[HTML][HTML] Mechanism of PARP inhibitor resistance and potential overcoming strategies

X Fu, P Li, Q Zhou, R He, G Wang, S Zhu, A Bagheri… - Genes & diseases, 2024 - Elsevier
PARP inhibitors (PARPi) are a kind of cancer therapy that targets poly (ADP-ribose)
polymerase. PARPi is the first clinically approved drug to exert synthetic lethality by …