AP endonuclease paralogues with distinct activities in DNA repair and bacterial pathogenesis

TY - JOUR

T1 - AP endonuclease paralogues with distinct activities in DNA repair and bacterial pathogenesis

AU - Carpenter, Elisabeth P

AU - Corbett, Anne

AU - Thomson, Hellen

AU - Adacha, Jolanta

AU - Jensen, Kirsten

AU - Bergeron, Julien

AU - Kasampalidis, Ioannis

AU - Exley, Rachel

AU - Winterbotham, Megan

AU - Tang, Christoph

AU - Baldwin, Geoff S

AU - Freemont, Paul

PY - 2007/3/7

Y1 - 2007/3/7

N2 - Oxidative stress is a principal cause of DNA damage, and mechanisms to repair this damage are among the most highly conserved of biological processes. Oxidative stress is also used by phagocytes to attack bacterial pathogens in defence of the host. We have identified and characterised two apurinic/apyrimidinic (AP) endonuclease paralogues in the human pathogen Neisseria meningitidis. The presence of multiple versions of DNA repair enzymes in a single organism is usually thought to reflect redundancy in activities that are essential for cellular viability. We demonstrate here that these two AP endonuclease paralogues have distinct activities in DNA repair: one is a typical Neisserial AP endonuclease (NApe), whereas the other is a specialised 3'-phosphodiesterase Neisserial exonuclease (NExo). The lack of AP endonuclease activity of NExo is shown to be attributable to the presence of a histidine side chain, blocking the abasic ribose-binding site. Both enzymes are necessary for survival of N. meningitidis under oxidative stress and during bloodstream infection. The novel functional pairing of NExo and NApe is widespread among bacteria and appears to have evolved independently on several occasions.

AB - Oxidative stress is a principal cause of DNA damage, and mechanisms to repair this damage are among the most highly conserved of biological processes. Oxidative stress is also used by phagocytes to attack bacterial pathogens in defence of the host. We have identified and characterised two apurinic/apyrimidinic (AP) endonuclease paralogues in the human pathogen Neisseria meningitidis. The presence of multiple versions of DNA repair enzymes in a single organism is usually thought to reflect redundancy in activities that are essential for cellular viability. We demonstrate here that these two AP endonuclease paralogues have distinct activities in DNA repair: one is a typical Neisserial AP endonuclease (NApe), whereas the other is a specialised 3'-phosphodiesterase Neisserial exonuclease (NExo). The lack of AP endonuclease activity of NExo is shown to be attributable to the presence of a histidine side chain, blocking the abasic ribose-binding site. Both enzymes are necessary for survival of N. meningitidis under oxidative stress and during bloodstream infection. The novel functional pairing of NExo and NApe is widespread among bacteria and appears to have evolved independently on several occasions.

KW - Amino Acid Sequence

KW - Amino Acid Substitution

KW - Animals

KW - Bacterial Proteins

KW - Blotting, Western

KW - Computational Biology

KW - Crystallography, X-Ray

KW - DNA Repair

KW - DNA-(Apurinic or Apyrimidinic Site) Lyase

KW - Histidine

KW - Humans

KW - Models, Molecular

KW - Molecular Sequence Data

KW - Mutagenesis, Site-Directed

KW - Mutation

KW - Neisseria meningitidis

KW - Oxidative Stress

KW - Phylogeny

KW - Protein Structure, Secondary

KW - Rats

KW - Rats, Wistar

KW - Sequence Alignment

KW - Virulence

U2 - 10.1038/sj.emboj.7601593

DO - 10.1038/sj.emboj.7601593

M3 - Article

C2 - 17318183

SN - 0261-4189

VL - 26

SP - 1363

EP - 1372

JO - The EMBO journal

JF - The EMBO journal

IS - 5

M1 - N/A

ER -