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DNA polymerase λ Loop1 variant yields unexpected gain-of-function capabilities in nonhomologous end-joining.
Kaminski, Andrea M; Chiruvella, Kishore K; Ramsden, Dale A; Bebenek, Katarzyna; Kunkel, Thomas A; Pedersen, Lars C.
Afiliación
  • Kaminski AM; Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, 111 TW Alexander Dr., Bldg 101, Research Triangle Park, NC 27709, USA.
  • Chiruvella KK; Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Ramsden DA; Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Bebenek K; Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, 111 TW Alexander Dr., Bldg 101, Research Triangle Park, NC 27709, USA.
  • Kunkel TA; Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, 111 TW Alexander Dr., Bldg 101, Research Triangle Park, NC 27709, USA.
  • Pedersen LC; Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, 111 TW Alexander Dr., Bldg 101, Research Triangle Park, NC 27709, USA. Electronic address: pederse2@niehs.nih.gov.
DNA Repair (Amst) ; 136: 103645, 2024 Apr.
Article en En | MEDLINE | ID: mdl-38428373
ABSTRACT
DNA polymerases lambda (Polλ) and mu (Polµ) are X-Family polymerases that participate in DNA double-strand break (DSB) repair by the nonhomologous end-joining pathway (NHEJ). Both polymerases direct synthesis from one DSB end, using template derived from a second DSB end. In this way, they promote the NHEJ ligation step and minimize the sequence loss normally associated with this pathway. The two polymerases differ in cognate substrate, as Polλ is preferred when synthesis must be primed from a base-paired DSB end, while Polµ is required when synthesis must be primed from an unpaired DSB end. We generated a Polλ variant (PolλKGET) that retained canonical Polλ activity on a paired end-albeit with reduced incorporation fidelity. We recently discovered that the variant had unexpectedly acquired the activity previously unique to Polµ-synthesis from an unpaired primer terminus. Though the sidechains of the Loop1 region make no contact with the DNA substrate, PolλKGET Loop1 amino acid sequence is surprisingly essential for its unique activity during NHEJ. Taken together, these results underscore that the Loop1 region plays distinct roles in different Family X polymerases.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: ADN Polimerasa beta / ADN Polimerasa Dirigida por ADN Idioma: En Revista: DNA Repair (Amst) Asunto de la revista: BIOLOGIA MOLECULAR / BIOQUIMICA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Países Bajos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: ADN Polimerasa beta / ADN Polimerasa Dirigida por ADN Idioma: En Revista: DNA Repair (Amst) Asunto de la revista: BIOLOGIA MOLECULAR / BIOQUIMICA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Países Bajos