DNA double-strand break processing
Definition
Target type: biologicalprocess
The 5' to 3' exonucleolytic resection of the DNA at the site of the break to form a 3' single-strand DNA overhang. [PMID:10357855]
DNA double-strand breaks (DSBs) are highly damaging lesions that can lead to genomic instability and cell death if not repaired properly. DSB repair is a complex and tightly regulated process involving multiple pathways, each with distinct mechanisms and outcomes. The two major pathways for DSB repair are:
1. Homologous recombination (HR): This pathway utilizes a homologous template, such as a sister chromatid, to accurately repair the break. HR is highly accurate and is typically active during S and G2 phases of the cell cycle when a sister chromatid is available. The process involves several key steps:
a. **Resection:** The 5' ends of the broken DNA strands are resected to generate 3' single-stranded tails.
b. **Strand invasion:** The 3' single-stranded tails invade the homologous template and form a displacement loop (D-loop).
c. **DNA synthesis:** Using the homologous template as a guide, DNA polymerase extends the invading strand, filling in the gap in the broken DNA.
d. **Branch migration:** The D-loop can migrate along the homologous template, extending the region of homology.
e. **Resolution:** The Holliday junctions formed during strand invasion are resolved by specific enzymes, resulting in two intact DNA molecules.
2. Non-homologous end joining (NHEJ): This pathway directly joins the broken ends of DNA without using a homologous template. NHEJ is less accurate than HR and can lead to small deletions or insertions at the repair site. However, NHEJ is active throughout the cell cycle, including G1 phase when a sister chromatid is not available. The process involves several key steps:
a. **End processing:** Broken DNA ends are often modified by nucleases or polymerases to create compatible overhangs.
b. **Synapsis:** The processed ends are brought together by specialized proteins, such as Ku70/80.
c. **Ligations:** The broken ends are ligated by DNA ligases, joining the two DNA fragments.
The choice between HR and NHEJ is influenced by several factors, including the cell cycle phase, the nature of the DNA damage, and the availability of a homologous template. Both HR and NHEJ are essential for maintaining genomic integrity and preventing disease. Defects in DSB repair pathways are linked to various human diseases, including cancer and neurodegenerative disorders.'
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Proteins (3)
| Protein | Definition | Taxonomy |
|---|---|---|
| Histone-lysine N-methyltransferase SETMAR | A histone-lysine N-methyltransferase SETMAR that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q53H47] | Homo sapiens (human) |
| Serine-protein kinase ATM | A serine-protein kinase ATM that is encoded in the genome of human. [PRO:CNA] | Homo sapiens (human) |
| Bloom syndrome protein | A RecQ-like DNA helicase BLM that is encoded in the genome of human. [PRO:DNx, UniProtKB:P54132] | Homo sapiens (human) |
Compounds (23)
| Compound | Definition | Classes | Roles |
|---|---|---|---|
| pd 173074 | aromatic amine; biaryl; dimethoxybenzene; pyridopyrimidine; tertiary amino compound; ureas | antineoplastic agent; EC 2.7.10.1 (receptor protein-tyrosine kinase) inhibitor; fibroblast growth factor receptor antagonist | |
| caffeine | purine alkaloid; trimethylxanthine | adenosine A2A receptor antagonist; adenosine receptor antagonist; adjuvant; central nervous system stimulant; diuretic; EC 2.7.11.1 (non-specific serine/threonine protein kinase) inhibitor; EC 3.1.4.* (phosphoric diester hydrolase) inhibitor; environmental contaminant; food additive; fungal metabolite; geroprotector; human blood serum metabolite; mouse metabolite; mutagen; plant metabolite; psychotropic drug; ryanodine receptor agonist; xenobiotic | |
| 2-(4-morpholinyl)-8-phenyl-4h-1-benzopyran-4-one | 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one: specific inhibitor of phosphatidylinositol 3-kinase; structure in first source | chromones; morpholines; organochlorine compound | autophagy inhibitor; EC 2.7.1.137 (phosphatidylinositol 3-kinase) inhibitor; geroprotector |
| schizandrin b | schizandrin B: a phytogenic antineoplastic agent with anti-inflammatory activity; isolated from Schisandra plant | ||
| 1-(3,4-dichlorophenyl)-3-(5-pyridin-4-yl-1,3,4-thiadiazol-2-yl)urea | ureas | ||
| thiourea | thiourea : The simplest member of the thiourea class, consisting of urea with the oxygen atom substituted by sulfur. Thiourea: A photographic fixative used also in the manufacture of resins. According to the Fourth Annual Report on Carcinogens (NTP 85-002, 1985), this substance may reasonably be anticipated to be a carcinogen (Merck Index, 9th ed). Many of its derivatives are ANTITHYROID AGENTS and/or FREE RADICAL SCAVENGERS. | one-carbon compound; thioureas; ureas | antioxidant; chromophore |
| ku 55933 | 2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one: specific inhibitor of the ataxia-telangiectasia mutated kinase ATM; structure in first source | ||
| cgk 733 | diarylmethane | ||
| nu 7026 | 2-(morpholin-4-yl)benzo(h)chromen-4-one: a radiosensitizing agent that inhibits DNA-dependent protein kinase; structure in first source | organic heterotricyclic compound; organooxygen compound | |
| nu 7441 | 8-dibenzothiophen-4-yl-2-morpholin-4-yl-chromen-4-one: structure in first source | dibenzothiophenes | |
| ku-0060648 | dibenzothiophenes | ||
| dactolisib | dactolisib : An imidazoquinoline that is 3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinoline substituted at position 1 by a 4-(1-cyanoisopropyl)phenyl group and at position 8 by a quinolin-3-yl group. A dual PI3K/mTOR inhibitor used in cancer treatment. dactolisib: antineoplastic agent that inhibits both phosphatidylinositol 3-kinase and mTOR | imidazoquinoline; nitrile; quinolines; ring assembly; ureas | antineoplastic agent; EC 2.7.1.137 (phosphatidylinositol 3-kinase) inhibitor; mTOR inhibitor |
| ku 60019 | |||
| cp 466722 | quinazolines | ||
| (3R)-4-[2-(1H-indol-4-yl)-6-(1-methylsulfonylcyclopropyl)-4-pyrimidinyl]-3-methylmorpholine | indoles | ||
| 1-[4-fluoro-3-(trifluoromethyl)phenyl]-3-(5-pyridin-4-yl-1,3,4-thiadiazol-2-yl)urea | ureas | ||
| ve 821 | 3-amino-6-(4-(methylsulfonyl)phenyl)-N-phenylpyrazine-2-carboxamide: an antineoplastic agent; structure in first source | aromatic amide | |
| torin 2 | torin 2 : A member of the class of pyridoquinolines that is benzo[h][1,6]naphthyridin-2-one carrying additional 3-(trifluoromethyl)phenyl and 6-aminopyridin-3-yl substituents at positions 1 and 9 respectively. It is a potent inhibitor of mTOR and exhibits anti-cancer properties. | aminopyridine; organofluorine compound; primary amino compound; pyridoquinoline | antineoplastic agent; mTOR inhibitor |
| byl719 | proline derivative | ||
| cc-115 | 1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino(2,3-b)pyrazin-2(1H)-one: an mTOR kinase inhibitor; structure in first source | ||
| vx-970 | berzosertib: an ATR kinase inhibitor | sulfonamide | |
| gsk343 | GSK343 : A member of the class of indazoles that is 1-isopropyl-1H-indazole-4-carboxamide in which the nitrogen of the carboxamide group is substituted by a (6-methyl-2-oxo-4-propyl-1,2-dihydropyridin-3-yl)methyl group and in which the indazole ring is substituted at position 6 by a 2-(4-methylpiperazin-1-yl)pyridin-4-yl group. A highly potent and selective EZH2 inhibitor (IC50 = 4 nM). GSK343: an EZH2 methyltransferase inhibitor | aminopyridine; indazoles; N-alkylpiperazine; N-arylpiperazine; pyridone; secondary carboxamide | antineoplastic agent; apoptosis inducer; EC 2.1.1.43 (enhancer of zeste homolog 2) inhibitor |
| etp-46464 | ETP-46464: inhibits ATM and Rad3-related kinase; structure in first source |