Regulation of DNA Double Strand Breaks Processing: Focus on Barriers

Marini, Federica; Rawal, Chetan C.; Liberi, Giordano; Pellicioli, Achille

doi:10.3389/fmolb.2019.00055

Cited by 49 publications

(52 citation statements)

References 85 publications

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“…During HR, BRCA1 inhibits 53BP1 from interacting with the chromatin near the broken DNA ends (Chapman et al, 2012;Densham et al, 2016). This permits extensive end-resection of the break by endo-and exonucleases such as MRE11, CtIP, DNA2, and EXO1, yielding 3 -single-stranded (ss) DNA overhangs that counter Ku loading and further promote DSB repair by HR (Marini et al, 2019). Following resection, the 3 -ssDNA tails become coated by the RPA heterotrimer (Symington, 2016).…”

Section: Palb2 Is Essential For Dna Repair By Homologous Recombinationmentioning

confidence: 99%

Functional Characterization of PALB2 Variants of Uncertain Significance: Toward Cancer Risk and Therapy Response Prediction

Boonen

Vreeswijk

Attikum

2020

Front. Mol. Biosci.

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In recent years it has become clear that pathogenic variants in PALB2 are associated with a high risk for breast, ovarian and pancreatic cancer. However, the clinical relevance of variants of uncertain significance (VUS) in PALB2, which are increasingly identified through clinical genetic testing, is unclear. Here we review recent advances in the functional characterization of VUS in PALB2. A combination of assays has been used to assess the impact of PALB2 VUS on its function in DNA repair by homologous recombination, cell cycle regulation and the control of cellular levels of reactive oxygen species (ROS). We discuss the outcome of this comprehensive analysis of PALB2 VUS, which showed that VUS in PALB2's Coiled-Coil (CC) domain can impair the interaction with BRCA1, whereas VUS in its WD40 domain affect PALB2 protein stability. Accordingly, the CC and WD40 domains of PALB2 represent hotspots for variants that impair PALB2 protein function. We also provide a future perspective on the high-throughput analysis of VUS in PALB2, as well as the functional characterization of variants that affect PALB2 RNA splicing. Finally, we discuss how results from these functional assays can be valuable for predicting cancer risk and responsiveness to cancer therapy, such as treatment with PARP inhibitor-or platinumbased chemotherapy.

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Section: Palb2 Is Essential For Dna Repair By Homologous Recombinationmentioning

confidence: 99%

Functional Characterization of PALB2 Variants of Uncertain Significance: Toward Cancer Risk and Therapy Response Prediction

Boonen

Vreeswijk

Attikum

2020

Front. Mol. Biosci.

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“…The critical difference between HR and NHEJ pathway choice is the requirement of end resection for HR, and the prevention of end resection for NHEJ, with end processing being very minimal in the NHEJ pathway in contrast to HR. Antagonism between 53BP1 (anti-resection) and BRCA1 (pro-resection), coupled with the cell cycle phase and other factors such as chromatin context and transcriptional status, helps dictate through which pathway the break is repaired [ 3 , 9 ]. Unlike HR, a homologous template is not a requirement for NHEJ, and NHEJ is active throughout the cell cycle [ 3 ].…”

Section: The Dna Damage Response and Double-strand Break Repairmentioning

confidence: 99%

Jack of all trades? The versatility of RNA in DNA double-strand break repair

Ketley

Gullerová

2020

Essays in Biochemistry

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Abstract The mechanisms by which RNA acts in the DNA damage response (DDR), specifically in the repair of DNA double-strand breaks (DSBs), are emerging as multifaceted and complex. Different RNA species, including but not limited to; microRNA (miRNA), long non-coding RNA (lncRNA), RNA:DNA hybrid structures, the recently identified damage-induced lncRNA (dilncRNA), damage-responsive transcripts (DARTs), and DNA damage-dependent small RNAs (DDRNAs), have been shown to play integral roles in the DSB response. The diverse properties of these RNAs, such as sequence, structure, and binding partners, enable them to fulfil a variety of functions in different cellular contexts. Additionally, RNA can be modified post-transcriptionally, a process which is regulated in response to cellular stressors such as DNA damage. Many of these mechanisms are not yet understood and the literature contradictory, reflecting the complexity and expansive nature of the roles of RNA in the DDR. However, it is clear that RNA is pivotal in ensuring the maintenance of genome integrity. In this review, we will discuss and summarise recent evidence which highlights the roles of these various RNAs in preserving genomic integrity, with a particular focus on the emerging role of RNA in the DSB repair response.

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“…Notably, RNA:DNA hybrids seem to contribute to the recruitment of repair factors [131][132][133][134][135][136][137][138][139][140] and to the control of DNA end resection [132,[137][138][139], the fundamental process creating 3 end ssDNA filaments needed for recombination [142]. However, how RNA:DNA hybrids impact on DSB processing and repair is still an open debate [143]. Indeed, while some data indicate that they promote resection [136,137,139], others suggest an anti-resection role [132,138] or no effect at all [134].…”

Section: Hybrids At Dsbsmentioning

confidence: 99%

One, No One, and One Hundred Thousand: The Many Forms of Ribonucleotides in DNA

Nava

Grasso

Sertic

et al. 2020

IJMS

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In the last decade, it has become evident that RNA is frequently found in DNA. It is now well established that single embedded ribonucleoside monophosphates (rNMPs) are primarily introduced by DNA polymerases and that longer stretches of RNA can anneal to DNA, generating RNA:DNA hybrids. Among them, the most studied are R-loops, peculiar three-stranded nucleic acid structures formed upon the re-hybridization of a transcript to its template DNA. In addition, polyribonucleotide chains are synthesized to allow DNA replication priming, double-strand breaks repair, and may as well result from the direct incorporation of consecutive rNMPs by DNA polymerases. The bright side of RNA into DNA is that it contributes to regulating different physiological functions. The dark side, however, is that persistent RNA compromises genome integrity and genome stability. For these reasons, the characterization of all these structures has been under growing investigation. In this review, we discussed the origin of single and multiple ribonucleotides in the genome and in the DNA of organelles, focusing on situations where the aberrant processing of RNA:DNA hybrids may result in multiple rNMPs embedded in DNA. We concluded by providing an overview of the currently available strategies to study the presence of single and multiple ribonucleotides in DNA in vivo.

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Regulation of DNA Double Strand Breaks Processing: Focus on Barriers

Cited by 49 publications

References 85 publications

Functional Characterization of PALB2 Variants of Uncertain Significance: Toward Cancer Risk and Therapy Response Prediction

Functional Characterization of PALB2 Variants of Uncertain Significance: Toward Cancer Risk and Therapy Response Prediction

Jack of all trades? The versatility of RNA in DNA double-strand break repair

One, No One, and One Hundred Thousand: The Many Forms of Ribonucleotides in DNA

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