A Role for Human DNA Polymerase λ in Alternative Lengthening of Telomeres.
DNA double-strand breaks (DSBs), extra-chromosomal telomeric repeats (ECTRs), promyelocytic leukemia (PML) bodies
alternative lengthening of telomeres (ALT), DNA polymerase λ
microhomology-mediated strand transfer (MMST) activity
telomere dysfunction-induced foci (TIFs), telomere stress
Journal
International journal of molecular sciences
ISSN: 1422-0067
Titre abrégé: Int J Mol Sci
Pays: Switzerland
ID NLM: 101092791
Informations de publication
Date de publication:
27 Feb 2021
27 Feb 2021
Historique:
received:
20
01
2021
revised:
13
02
2021
accepted:
23
02
2021
entrez:
6
3
2021
pubmed:
7
3
2021
medline:
5
5
2021
Statut:
epublish
Résumé
Telomerase negative cancer cell types use the Alternative Lengthening of Telomeres (ALT) pathway to elongate telomeres ends. Here, we show that silencing human DNA polymerase (Pol λ) in ALT cells represses ALT activity and induces telomeric stress. In addition, replication stress in the absence of Pol λ, strongly affects the survival of ALT cells. In vitro, Pol λ can promote annealing of even a single G-rich telomeric repeat to its complementary strand and use it to prime DNA synthesis. The noncoding telomeric repeat containing RNA TERRA and replication protein A negatively regulate this activity, while the Protection of Telomeres protein 1 (POT1)/TPP1 heterodimer stimulates Pol λ. Pol λ associates with telomeres and colocalizes with TPP1 in cells. In summary, our data suggest a role of Pol λ in the maintenance of telomeres by the ALT mechanism.
Identifiants
pubmed: 33673424
pii: ijms22052365
doi: 10.3390/ijms22052365
pmc: PMC7956399
pii:
doi:
Substances chimiques
ACD protein, human
0
Multiprotein Complexes
0
POT1 protein, human
0
Replication Protein A
0
Shelterin Complex
0
Telomere-Binding Proteins
0
DNA polymerase beta2
EC 2.7.7.-
DNA Polymerase beta
EC 2.7.7.7
Serine Proteases
EC 3.4.-
Aminopeptidases
EC 3.4.11.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Associazione Italiana per la Ricerca sul Cancro
ID : IG20762
Organisme : Associazione Italiana per la Ricerca sul Cancro
ID : MFAG2016 18811
Organisme : Fondazione Italiana per la Ricerca sul Cancro
ID : 24263
Organisme : Associazione Italiana per la Ricerca sul Cancro
ID : Start-up Grant 12710
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