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DNA damage in oocytes induces a switch of the quality control factor TAp63? from dimer to tetramer.

ABSTRACT: TAp63?, a homolog of the p53 tumor suppressor, is a quality control factor in the female germline. Remarkably, already undamaged oocytes express high levels of the protein, suggesting that TAp63?'s activity is under tight control of an inhibitory mechanism. Biochemical studies have proposed that inhibition requires the C-terminal transactivation inhibitory domain. However, the structural mechanism of TAp63? inhibition remains unknown. Here, we show that TAp63? is kept in an inactive dimeric state. We reveal that relief of inhibition leads to tetramer formation with ?20-fold higher DNA affinity. In vivo, phosphorylation-triggered tetramerization of TAp63? is not reversible by dephosphorylation. Furthermore, we show that a helix in the oligomerization domain of p63 is crucial for tetramer stabilization and competes with the transactivation domain for the same binding site. Our results demonstrate how TAp63? is inhibited by complex domain-domain interactions that provide the basis for regulating quality control in oocytes.

SUBMITTER: Deutsch GB

PROVIDER: S-EPMC3087504 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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DNA damage in oocytes induces a switch of the quality control factor TAp63α from dimer to tetramer.

Deutsch Gregor B GB Zielonka Elisabeth M EM Coutandin Daniel D Weber Tobias A TA Schäfer Birgit B Hannewald Jens J Luh Laura M LM Durst Florian G FG Ibrahim Mohamed M Hoffmann Jan J Niesen Frank H FH Sentürk Aycan A Kunkel Hana H Brutschy Bernd B Schleiff Enrico E Knapp Stefan S Acker-Palmer Amparo A Grez Manuel M McKeon Frank F Dötsch Volker V

Cell 20110201 4

TAp63α, a homolog of the p53 tumor suppressor, is a quality control factor in the female germline. Remarkably, already undamaged oocytes express high levels of the protein, suggesting that TAp63α's activity is under tight control of an inhibitory mechanism. Biochemical studies have proposed that inhibition requires the C-terminal transactivation inhibitory domain. However, the structural mechanism of TAp63α inhibition remains unknown. Here, we show that TAp63α is kept in an inactive dimeric stat ...[more]

PMID: 21335238

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Project description:The ground-state properties of (NO)(2) and (NO)(4) have been investigated using multireference second-order perturbation theory (MRMP2) and include a two-tier extrapolation to the complete basis set (CBS) limit. For the NO dimer the MRMP2(18,14)/CBS predicted structure, binding energy (with respect to 2NO; D(e) = 3.46 kcal/mol), and dipole moment (u(e) = 0.169 D) are in excellent agreement with experimental measurements (D(e) = 2.8-3.8 kcal/mol; u(e) = 0.171 D). Additionally, three of four intermolecular anharmonic MRMP2(18,14)/CBS-estimated frequencies (143 cm(-1), 238 cm(-1), 421 cm(-1)) are in excellent agreement with recent gas-phase experimental measurements (135 cm(-1), 239 cm(-1), 429/428 cm(-1)); however, the predicted value of 151 cm(-1) for the out-of-plane torsion (A(2)) is elevated compared to recent experimental estimates of 97-117 cm(-1). Our finding that this infrared-forbidden vibration is also predicted to have an extremely low Raman activity (0.04 Å/amu at the MP2/QZ level of theory) conflicts with Raman measurements of a strong intensity for a low frequency band; however, these studies were performed for low temperature solid and liquid phases. Probing the possibility of the presence of higher order clusters we investigated the stability of (NO)(4) and discovered three isomers, each resembling pairs of dimers, that were stable to dissociation to 2(NO)(2), with the lowest-energy isomer (C(i) structure) having a predicted binding energy almost identical to that of the dimer. Computed vibrational frequencies of the C(i) isomer indicate that the 12 highest-frequency modes resemble barely shifted NO dimer-combined bands while the 13th highest-frequency mode at ~100 cm(-1) is exclusive to (NO)(4). Moreover, this tetramer-unique vibration is infrared inactive but has a very high predicted Raman activity of some 24 Å/amu. Guided by the theoretical results, we reexamined and reassigned experimental Raman and infrared data going back to 1951 and determined that our best predictions of vibrational frequencies of (NO)(2) and (NO)(4) are consistent with experimental observations. We thus postulate the existence and observation of (NO)(4).

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DNA damage in oocytes induces a switch of the quality control factor TAp63? from dimer to tetramer.

Publications

DNA damage in oocytes induces a switch of the quality control factor TAp63α from dimer to tetramer.

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