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#DNA repair

66 public questions tagged with this topic.

Cell Division

The G2 phase is characterized by:

G2 phase is second gap phase dedicated to growth, quality surveillance, and accumulation of components required for mitosis. After S phase completes DNA synthesis, cells continue protein synthesis, particularly tubulin alpha/beta heterodimers and gamma-tubulin ring complex proteins for spindle assembly, histone variants H2AZ for chromatin stability, and membrane lipid synthesis for organelle expansion. Centrosomes duplicated during S phase mature in G2 by recruitment of pericentriolar material including pericentrin, Cep192, and Cdk5Rap2, acquiring ability to nucleate large astral microtubule arrays. Mitochondria undergo fusion driven by mitofusins to enhance ATP production for mitosis. Simultaneously DNA damage checkpoint kinase ATR monitors incomplete replication intermediates and stalled forks, maintaining cyclin B-CDK1 inactive via Wee1 mediated Tyr15 phosphorylation until genome fully duplicated. Transcription of mitotic cyclin B and Polo-like kinase rises, preparing wave of mitotic entry. G2 thus bridges synthesis and segregation, ensuring daughters inherit intact genome and sufficient cytoplasm. This circuitry is highly conserved across eukaryotes, integrating growth factor signals, DNA damage surveillance, and developmental cues, and its disruption frequently underlies oncogenesis, providing targets for checkpoint inhibitors and cancer therapeutics.

Ref: Alberts et al., Molecular Biology of the Cell, 7th ed., Chapter 17, G2 as Preparation for M Phase.

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Cell Cycle Regulation

Which DNA repair pathway is activated by ATM after detecting double-strand breaks?

Double-strand breaks present challenging repair choice between rapid but error-prone non-homologous end joining and accurate homologous recombination available only when sister chromatid present. ATM kinase activated by MRN complex phosphorylates H2AX, creating gamma-H2AX domains that recruit mediator 53BP1, which in turn favors end joining by blocking resection. In G1 phase when homologous template absent, ATM-53BP1 axis directs breaks toward classical non-homologous end joining pathway that directly ligates ends after minimal processing by Ku70/Ku80 heterodimer, DNA-PKcs, and XRCC4-DNA ligase IV complex. This pathway can operate throughout cell cycle but dominates in G1, preserving genome stability at cost of small deletions. Base excision repair handles oxidized bases via glycosylases like OGG1, nucleotide excision repair removes bulky UV adducts via XPA-XPC factors, mismatch repair corrects mispaired bases post-replication via MutS homologs, none directly activated by ATM for DSBs. Thus ATM orchestrates DSB response favoring NHEJ in G1 through histone modifications and mediator recruitment, while also signaling through CHK2-p53 to arrest cell cycle until repair completes or apoptosis initiated if damage excessive.

Ref: Marechal & Zou, Genes Dev 2013, DNA Damage Response; Scully et al., Cell 2019, DSB Repair Choice.

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Cell Cycle Regulation

Which component of the DNA damage response (DDR) is associated with single-strand DNA breaks?

Different lesions within DNA damage response activate distinct kinase cascades tailored to repair requirements. Single-strand breaks, gaps, and regions of single-stranded DNA generated when replication forks stall at UV photoproducts or chemical adducts expose stretches of RPA-coated ssDNA that recruit ATR-ATRIP complex and auxiliary proteins TopBP1 and ETAA1. ATR, ataxia telangiectasia and Rad3-related kinase, then phosphorylates CHK1 at serine 317 and 345, leading to degradation of Cdc25A and inhibition of CDK2 to slow S-phase progression and allow repair via homologous recombination or translesion synthesis. Double-strand breaks instead predominantly activate ATM-CHK2 axis. Mad2 participates in spindle assembly checkpoint rather than DNA damage. Recognizing that ATR responds to single-strand breaks is clinically relevant because ATR inhibitors are in trials as synthetic lethal agents with defective homologous recombination in tumors, exploiting replication stress and generating collapsed forks that require ATR for survival. Therefore association of ATR with ssDNA distinguishes it from ATM which governs DSB sensing. This mechanistic insight is relevant for competitive examinations such as CSIR-NET and GATE, where understanding molecular detail rather than memorization enables accurate interpretation of experimental data and pathway interconnections.

Ref: Cimprich & Cortez, Nature Rev Mol Cell Biol 2008, ATR: Essential Regulator of Genome Integrity; Zou & Elledge, Science 2003, ATR Activation.

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Repair Pathway

Transcription-coupled NER repairs damage on

Transcription-coupled nucleotide excision repair is subpathway accelerating removal of bulky helix-distorting lesions that block elongating RNA polymerase. When RNA polymerase II stalls at cyclobutane pyrimidine dimer or 6-4 photoproduct located on transcribed template strand, stalled complex is recognized by CSB and CSA ubiquitin ligase recruiting TFIIH and core excision factors. Repair focused exclusively on template strand because non-transcribed strand lesions do not impede polymerase translocation. This strand-specific prioritization ensures rapidly transcribed essential genes restored preferentially, explaining clinical features of Cockayne syndrome defective in this pathway versus global genome repair.

Ref: Watson Molecular Biology of Gene 7th ed. Chapter 10: TCR repairs template strand lesions; Alberts Ch.5 Transcription-coupled NER

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