Mutants of the tumour suppressor p53 L1 loop as second-site suppressors for restoring DNA binding to oncogenic p53 mutations: structural and biochemical insights
Authors: Hellen Houlleberghs
Kate Maclagan
Tam T T Bui
Assia Merabet
Ester Akanho
Bruno Pagano
Penka V Nikolova
Franca Fraternali
Alex F Drake
Journal: Biochemical Journal (2010)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: mutations; L1 loop; tumour suppressor p53; second-site suppressors; H115N
Affiliations: Department of Biochemistry, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH, U.K., Randall Division of Cell and Molecular Biophysics, King's College London, New Hunts House, London, SE1 1UL, U.K., Dipartimento di Scienze Farmaceutiche, Universita di Salerno, via Ponte Don Melillo, Fisciano (SA) I-84084, Italy

Abstract:  To assess the potential of mutations from the L1 loop of the tumour suppressor p53 as second-site suppressors, the effect of H115N and S116M on the p53 'hot spot' mutations has been investigated using the double-mutant approach. The effects of these two mutants on the p53 hot spots in terms of thermal stability and DNA binding were evaluated. The results show that: (i) the p53 mutants H115N and S116M are thermally more stable than wild-type p53; (ii) H115N but not S116M is capable of rescuing the DNA binding of one of the most frequent p53 mutants in cancer, R248Q, as shown by binding of R248Q/H115N to gadd45 (the promoter of a gene involved in cell-cycle arrest); (iii) the double mutant R248Q/H115N is more stable than wild-type p53; (iv) the effect of H115N as a second-site suppressor to restore DNA-binding activity is specific to R248Q, but not to R248W; (v) molecular-dynamics simulations indicate that R248Q/H115N has a conformation similar to wild-type p53, which is distinct from that of R248Q. These findings could be exploited in designing strategies for cancer therapy to identify molecules that could mimic the effect of H115N in restoring function to oncogenic p53 mutants. 

Retracted: No

PubPeer comments:
 Correction, [January 2019] - though the correction could be summed up as  ignore the advice provided in the article , so it might as well be a Retraction. ------------------------ Recommendations in 2 articles published in Canadian Family Physician, u201cNausea and vomiting of pregnancy. Evidence-based treatment algorithmu201d1 and u201cTreatment of nausea and vomiting in pregnancy. An updated algorithm,u201d2 have subsequently come under critical scrutiny.3,4 These articles were not subjected to standard peer review, and Canadian Family Physician acknowledges that upon closer inspection these articles did not provide satisfactory evidence that would have justified the recommendation of doxylamine-pyridoxine as a sole first-line treatment for nausea and vomiting in pregnancy (NVP). More recent Canadian NVP guidelines have been published5; however, a subsequent re-analysis6 questions the conclusions of 1 of the studies7 cited in these guidelines to justify doxylamine-pyridoxine as a recommended first-line treatment for NVP. Additionally, for the articles in Canadian Family Physician1,2 there was an undisclosed conflict of interest with Duchesnay, the manufacturer of Diclectin, the combination of doxylamine-pyridoxine. Canadian Family Physician encourages readers to interpret previously published NVP recommendations with caution. Readers are also referred to the commentary u201cMotherisk and Canadian Family Physicianu201d in the January 2017 issue of Canadian Family Physician.8 - [1]. Levichek Z, Atanackovic G, Oepkes D, Maltepe C, Einarson A, Magee L, et al. Nausea and vomiting of pregnancy. Evidence-based treatment algorithm. Can Fam Physician. 2002;48:267u20138. 277. - [2]. Einarson A, Maltepe C, Boskovic R, Koren G. Treatment of nausea and vomiting in pregnancy. An updated algorithm. Can Fam Physician. 2007;53:2109u201311. - [3]. Chin JWS, Gregor S, Persaud N. Re-analysis of safety data supporting doxylamine use for nausea and vomiting of pregnancy. Am J Perinatol. 2014;31(8):701u201310. Epub 2013 Dec 9. - [4]. Persaud N, Chin J, Walker M. Should doxylamine-pyridoxine be used for nausea and vomiting of pregnancy? J Obstet Gynaecol Can. 2014;36(4):343u20138. - [5]. Campbell K, Rowe H, Azzam H, Lane CA. The management of nausea and vomiting of pregnancy. J Obstet Gynaecol Can. 2016;38(12):1127u201337. - [6]. Persaud N, Meaney C, El-Emam K, Moineddin R, Thorpe K. Doxylamine-pyridoxine for nausea and vomiting of pregnancy randomized placebo controlled trial: prespecified analyses and reanalysis. PLoS One. 2018;13(1):e0189978. - [7]. Koren G, Clark S, Hankins GD, Caritis SN, Miodovnik M, Umans JG, et al. Effectiveness of delayed-release doxylamine and pyridoxine for nausea and vomiting of pregnancy: a randomized placebo controlled trial. Am J Obstet Gynecol. 2010;203(6):571.e1u20137. Epub 2010 Sep 16. - [8]. Pimlott N, Kvern B, Woollard R. Motherisk and Canadian Family Physician. Can Fam Physician. 2017;63:13u20134. (Eng), e1u20132 (Fr). ,