Details

Autor(en) / Beteiligte

• Chakraborty, Anirban
• Wakamiya, Maki
• Venkova-Canova, Tatiana
• Pandita, Raj K.
• Aguilera-Aguirre, Leopoldo
• Sarker, Altaf H.
• Singh, Dharmendra Kumar
• Hosoki, Koa
• Wood, Thomas G.
• Sharma, Gulshan
• Cardenas, Victor
• Sarkar, Partha S.
• Sur, Sanjiv
• Pandita, Tej K.
• Boldogh, Istvan
• Hazra, Tapas K.

Titel

Neil2-null Mice Accumulate Oxidized DNA Bases in the Transcriptionally Active Sequences of the Genome and Are Susceptible to Innate Inflammation

Ist Teil von

• The Journal of biological chemistry, 2015-10, Vol.290 (41), p.24636-24648

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2015

Quelle

MEDLINE

Beschreibungen/Notizen

• Why mammalian cells possess multiple DNA glycosylases (DGs) with overlapping substrate ranges for repairing oxidatively damaged bases via the base excision repair (BER) pathway is a long-standing question. To determine the biological role of these DGs, null animal models have been generated. Here, we report the generation and characterization of mice lacking Neil2 (Nei-like 2). As in mice deficient in each of the other four oxidized base-specific DGs (OGG1, NTH1, NEIL1, and NEIL3), Neil2-null mice show no overt phenotype. However, middle-aged to old Neil2-null mice show the accumulation of oxidative genomic damage, mostly in the transcribed regions. Immuno-pulldown analysis from wild-type (WT) mouse tissue showed the association of NEIL2 with RNA polymerase II, along with Cockayne syndrome group B protein, TFIIH, and other BER proteins. Chromatin immunoprecipitation analysis from mouse tissue showed co-occupancy of NEIL2 and RNA polymerase II only on the transcribed genes, consistent with our earlier in vitro findings on NEIL2's role in transcription-coupled BER. This study provides the first in vivo evidence of genomic region-specific repair in mammals. Furthermore, telomere loss and genomic instability were observed at a higher frequency in embryonic fibroblasts from Neil2-null mice than from the WT. Moreover, Neil2-null mice are much more responsive to inflammatory agents than WT mice. Taken together, our results underscore the importance of NEIL2 in protecting mammals from the development of various pathologies that are linked to genomic instability and/or inflammation. NEIL2 is thus likely to play an important role in long term genomic maintenance, particularly in long-lived mammals such as humans. Background: NEIL2 (Nei-like 2) is a mammalian oxidized base-specific DNA glycosylase. Results:Neil2-null mice accumulate oxidative damage in transcribed genes and are susceptible to inflammatory agents. Conclusion: In long-lived species, NEIL2 plays a critical role in maintaining genomic integrity and tissue homeostasis. Significance: We provide in vivo evidence for NEIL2's role in preferential repair of oxidized bases in active genes in mammals.