Fhit and CHK1 have opposing effects on homologous recombination repair
Authors: Kay Huebner
Ya Wang
Hongyan Wang
Simon N Powell
Xiang Wang
Baocheng Hu
Cuifen Huang
Hua-Rui Lu
Journal: Cancer research (2005)
Discipline: CLINICAL MEDICINE
Keywords: Fragile histidine triad; FHIT gene; promoter methylation; Fhit protein expression; ATR/CHK1 pathway
Affiliations: Beijing Institute of Biotechnology, Beijing, China.

Abstract:  Fragile histidine triad (FHIT) gene deletion or promoter methylation and reduced Fhit protein expression occur in approximately 70% of human epithelial tumors and, in some cancers, are clearly associated with tumor progression. Specific Fhit signal pathways have not been identified. We previously reported that compared with Fhit+/+ cells, Fhit-/- cells with an overactivated ATR/CHK1 pathway show increased mutation frequency and resistance to DNA damage-induced killing, indicating that Fhit and the CHK1 pathway have opposing roles in cells responding to DNA damage. In this study, we show that cells, with or without Fhit expression, have similar DNA double-strand break induction levels and similar rejoining rates following ionizing radiation, indicating that the effect of Fhit on cell radiosensitivity is independent of nonhomologous end-joining. By combining I-SceI-induced-DNA double-strand break system and small interfering RNA approach, we also show that knocking down Fhit increases the efficiency of homologous recombination repair of cells, but knocking down Chk1 decreases the efficiency of homologous recombination repair, associated with the sensitivity to ionizing radiation-induced killing. Taken together, the results show that the role of Fhit in affecting the sensitivity of cells to ionizing radiation-induced killing is through the CHK1 pathway linked to homologous recombination repair. These results also illustrate the importance of balanced checkpoint activation in genomic stability and suggest a connection between the radioresistance and mutagenesis, carcinogenesis, as well as tumor progression in Fhit-deficient cells or tissue. 

Retracted: No

PubPeer comments:
 Figure 2. Control Fhit siRNA and control Chk1 siRNA panels are more similar than you would expect. , 
 Figure 3A. CHK1 panel. Bands lanes 4 and 5 look like bands lanes 1 and 2. PCNA panel. Bands lanes 4 to 6 look like bands lanes 1 to 3. , 
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 Much more similar than you would expect even though the experiments are different. https: imgur.com GG619JU , 
 Jan 26, 2020 Thanks for the carefully checking, I just saw this email from junk folder, I might have missed your previous emails. I am surprised for the figures published in 2006 identical to that shown in our publication in 2005. I immediately checked the CHK1 and Hus1 images in the 2006 submitted folder, they showed different from those shown in the publication, I attached them here: CHK1: [file] Hus1: [file] I believe that this mistake that happened when we submitted the manuscript by sending wrong images. Sorry for the mistake, I am the corresponding author and I should be responsible for it. Welcome more comments! I will reply them when I receive the comments. , 
 #6 There s more to it than just the CHK1 and Hus1 panels. How to explain the CHK1 panel in the 2006 publication being very similar to a horizontally stretched version of the PCNA panel in the 2005 paper? , 
 #7 As I mentioned, this is because we sent wrong image to Oncogene in 2006, we found the mistake after this paper was published, then we corrected the mistake by sending the right image to the journal, which has been published. Please see the attachment.  , 
 #8 Figures 2B and 3A of this paper (Cancer Res 2005) look like they have features which are very similar. A correction in Oncogene does not address that. The electronic version of the 2008 correction to figure 3a of the 2006 Oncogene paper. https: www.nature.com articles onc20081 Corrected 3a: https: imgur.com SFocSxI ,