Regulation of Error-Prone DNA Double-Strand Break Repair and Its Impact on Genome Evolution

Hanscom, Terrence; McVey, Mitch

doi:10.3390/cells9071657

Cited by 51 publications

(52 citation statements)

References 145 publications

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“…Tumor cells experience an overload of replication stress which leads to DNA damage [ 97 ]. In these circumstances, cancer cells often rely on error-prone DNA repair that allows survival by increasing the mutagenic rate, which in turn promotes genomic instability, disease progression and drug resistance [ 98 , 99 ]. In this review, we describe the pivotal role exerted by Alt-NHEJ, an error-prone DNA repair acting as back-up process when major DSB repair pathways fail.…”

Section: Discussionmentioning

confidence: 99%

Alternative Non-Homologous End-Joining: Error-Prone DNA Repair as Cancer’s Achilles’ Heel

Caracciolo

Riillo

Martino

et al. 2021

Cancers

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Error-prone DNA repair pathways promote genomic instability which leads to the onset of cancer hallmarks by progressive genetic aberrations in tumor cells. The molecular mechanisms which foster this process remain mostly undefined, and breakthrough advancements are eagerly awaited. In this context, the alternative non-homologous end joining (Alt-NHEJ) pathway is considered a leading actor. Indeed, there is experimental evidence that up-regulation of major Alt-NHEJ components, such as LIG3, PolQ, and PARP1, occurs in different tumors, where they are often associated with disease progression and drug resistance. Moreover, the Alt-NHEJ addiction of cancer cells provides a promising target to be exploited by synthetic lethality approaches for the use of DNA damage response (DDR) inhibitors and even as a sensitizer to checkpoint-inhibitors immunotherapy by increasing the mutational load. In this review, we discuss recent findings highlighting the role of Alt-NHEJ as a promoter of genomic instability and, therefore, as new cancer’s Achilles’ heel to be therapeutically exploited in precision oncology.

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Section: Discussionmentioning

confidence: 99%

Alternative Non-Homologous End-Joining: Error-Prone DNA Repair as Cancer’s Achilles’ Heel

Caracciolo

Riillo

Martino

et al. 2021

Cancers

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“…Double strand break (DSB) is a mechanism used in experiments of DNA rearrangements to cure serious illnesses like cancer but it is also a tool in spontaneous DNA reshufflings leading to evolutionary novelties. In a recent review both experimental and spontaneous DSB are extensively treated [43]. In hundreds of million years of evolutionary history, DSB played a critical role in the pathway from simple ontological structures to more complex entities.…”

Section: Circular Organization Of Echinoderms At Different Developmental Stagesmentioning

confidence: 99%

Physical Laws shape up HOX Gene Collinearity

Papageorgiou¹

2021

Preprint

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Hox gene collinearity (HGC) is a multiscalar property of many animal phyla particularly important in embryogenesis. It relates entities and events occurring in Hox clusters inside the chromosome DNA and in embryonic tissues. These two entities differ in linear size by more than four orders of magnitude. HGC is observed as spatial collinearity (SC) where the Hox genes are located in the order (Hox1, Hox2, Hox3 …) along the 3’ to 5’ direction of DNA in the genome and a corresponding sequence of ontogenetic units (E1, E2, E3, …) located along the Anterior – Posterior axis of the embyo. Expression of Hox1 occurs in E1. Hox2 in E2, Hox3 in E3… Besides SC, a temporal collinearity (TC) has been also observed in many vertebrates. According to TC first is Hox1 expressed in E1, later is Hox2 expressed in E2, followed by Hox3 in E3,… Lately doubt has been raised whether TC really exists. A biophysical model (BM) was formulated and tested during the last twenty years. According to BM, physical forces are created which pull the Hox genes one after the other driving them to a transcription factory domain where they are transcribed. The existing experiments support this BM description. Symmetry is a physical-mathematical property of Matter that was explored in depth by Noether who formulated a ground-breaking theory that applies to all sizes of Matter. This theory applied to Biology can explain the origin of HGC as applied not only to animals developing along the A/P axis but also to animals with circular symmetry.

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“…MMEJ, like HR, needs free 3’-OH ends tails, although they are extremely short (as short as 2 bps). MMEJ is dependent of a DNA polymerase that anneals the micro-homologous regions and uses them as a template [ 96 , 97 , 98 ]. In animals, MMEJ is limited to DNA polymerases λ, β , and θ [ 34 , 64 , 99 ].…”

Section: Plant Organellar Dna Polymerase Accomplish Micro-homologymentioning

confidence: 99%

Plant Organellar DNA Polymerases Evolved Multifunctionality through the Acquisition of Novel Amino Acid Insertions

Peralta-Castro

García‐Medel

Baruch‐Torres

et al. 2020

Genes

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The majority of DNA polymerases (DNAPs) are specialized enzymes with specific roles in DNA replication, translesion DNA synthesis (TLS), or DNA repair. The enzymatic characteristics to perform accurate DNA replication are in apparent contradiction with TLS or DNA repair abilities. For instance, replicative DNAPs incorporate nucleotides with high fidelity and processivity, whereas TLS DNAPs are low-fidelity polymerases with distributive nucleotide incorporation. Plant organelles (mitochondria and chloroplast) are replicated by family-A DNA polymerases that are both replicative and TLS DNAPs. Furthermore, plant organellar DNA polymerases from the plant model Arabidopsis thaliana (AtPOLIs) execute repair of double-stranded breaks by microhomology-mediated end-joining and perform Base Excision Repair (BER) using lyase and strand-displacement activities. AtPOLIs harbor three unique insertions in their polymerization domain that are associated with TLS, microhomology-mediated end-joining (MMEJ), strand-displacement, and lyase activities. We postulate that AtPOLIs are able to execute those different functions through the acquisition of these novel amino acid insertions, making them multifunctional enzymes able to participate in DNA replication and DNA repair.

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Regulation of Error-Prone DNA Double-Strand Break Repair and Its Impact on Genome Evolution

Cited by 51 publications

References 145 publications

Alternative Non-Homologous End-Joining: Error-Prone DNA Repair as Cancer’s Achilles’ Heel

Alternative Non-Homologous End-Joining: Error-Prone DNA Repair as Cancer’s Achilles’ Heel

Physical Laws shape up HOX Gene Collinearity

Plant Organellar DNA Polymerases Evolved Multifunctionality through the Acquisition of Novel Amino Acid Insertions

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