A Role for Human DNA Polymerase λ in Alternative Lengthening of Telomeres

Int J Mol Sci. 2021 Feb 27;22(5):2365. doi: 10.3390/ijms22052365.


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.

Keywords: 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.

MeSH terms

  • Aminopeptidases / metabolism*
  • Cell Line, Tumor
  • DNA Polymerase beta / metabolism*
  • G-Quadruplexes*
  • Humans
  • Multiprotein Complexes
  • Replication Protein A / metabolism
  • Serine Proteases / metabolism*
  • Shelterin Complex
  • Telomere / chemistry
  • Telomere / metabolism
  • Telomere Homeostasis*
  • Telomere-Binding Proteins / metabolism*


  • ACD protein, human
  • Multiprotein Complexes
  • POT1 protein, human
  • Replication Protein A
  • Shelterin Complex
  • Telomere-Binding Proteins
  • DNA polymerase beta2
  • DNA Polymerase beta
  • Serine Proteases
  • Aminopeptidases