7UN7

DNA Polymerase lambda in complex with a 1nt microhomology substrate

Summary for 7UN7

• Entry DOI: 10.2210/pdb7un7/pdb
• Descriptor: DNA polymerase lambda, 1,2-ETHANEDIOL, DNA (5'-D(*CP*GP*GP*CP*AP*GP*T)-3'), ... (11 entities in total)
• Functional Keywords: replication
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 44271.13

Authors

Jamsen, J.A. (deposition date: 2022-04-09, release date: 2023-03-29, Last modification date: 2023-10-25)

Primary citation

Chandramouly, G.,Jamsen, J.,Borisonnik, N.,Tyagi, M.,Calbert, M.L.,Tredinnick, T.,Ozdemir, A.Y.,Kent, T.,Demidova, E.V.,Arora, S.,Wilson, S.H.,Pomerantz, R.T.
Pol lambda promotes microhomology-mediated end-joining.
Nat.Struct.Mol.Biol., 30:107-114, 2023

PubMed Abstract: The double-strand break (DSB) repair pathway called microhomology-mediated end-joining (MMEJ) is thought to be dependent on DNA polymerase theta (Polθ) and occur independently of nonhomologous end-joining (NHEJ) factors. An unresolved question is whether MMEJ is facilitated by a single Polθ-mediated end-joining pathway or consists of additional undiscovered pathways. We find that human X-family Polλ, which functions in NHEJ, additionally exhibits robust MMEJ activity like Polθ. Polλ promotes MMEJ in mammalian cells independently of essential NHEJ factors LIG4/XRCC4 and Polθ, which reveals a distinct Polλ-dependent MMEJ mechanism. X-ray crystallography employing in situ photo-induced DSB formation captured Polλ in the act of stabilizing a microhomology-mediated DNA synapse with incoming nucleotide at 2.0 Å resolution and reveals how Polλ performs replication across a DNA synapse joined by minimal base-pairing. Last, we find that Polλ is semisynthetic lethal with BRCA1 and BRCA2. Together, these studies indicate Polλ MMEJ as a distinct DSB repair mechanism.

PubMed: 36536104
DOI: 10.1038/s41594-022-00895-4

Experimental method

X-RAY DIFFRACTION (2.04 Å)