Preprint Article Version 1 This version not peer reviewed

Revealing ETC-1922159 Affected Unknown 3rd Order Combinations of DNA Repair & Genomic Stability Factor RAD51 Family, in Silico

Version 1 : Received: 30 October 2017 / Approved: 1 November 2017 / Online: 1 November 2017 (05:08:04 CET)

How to cite: sinha, S. Revealing ETC-1922159 Affected Unknown 3rd Order Combinations of DNA Repair & Genomic Stability Factor RAD51 Family, in Silico. Preprints 2017, 2017110008 (doi: 10.20944/preprints201711.0008.v1). sinha, S. Revealing ETC-1922159 Affected Unknown 3rd Order Combinations of DNA Repair & Genomic Stability Factor RAD51 Family, in Silico. Preprints 2017, 2017110008 (doi: 10.20944/preprints201711.0008.v1).

Abstract

DNA repair helps in maintaining the proper and healthy functioning for the cells in the human body. Failure in DNA repair process can lead to aberrations as well as tumorous stages. There are various types of damages that a DNA can go through, one of which is the DNA double strand breaks (DSB) that can be repaired via homologous recombination (HR). RAD51 plays a central role in HR and has been implicated as a negative/poor prognostic marker for colorectal adenocarcinoma, with high expression in colorectal cancer. Mechanistically, RAD51AP1 facilitates RAD51 during the repairing process by binding with RAD51 via two DNA binding sites, thus helping in the D-loop formation in the HR process. Often, in biology, we are faced with the problem of exploring relevant unknown biological hypotheses in the form of myriads of combination of factors that might be affecting the pathway under certain conditions. For example, RAD51AP1-XRCC2 is one such 2nd order combination whose relation needs to be tested under the influence recently developed Porcupine-WNT inhibitor ETC-1922159. The x-ray repair cross complementing XRCC family is known to work as a mediator or stabilizer for RAD51 during the HR process. The inhibitor is known to suppress Porcupine and thus inhibit a range of oncogenes known to be directly or indirectly affected by the Wnts. In a recent unpublished work in bioRxiv, we had the opportunity to rank these unknown biological hypotheses for down regulated genes at 2nd order level after the drug was administered. The in silico observations showed that the combination of RAD51AP1-XRCC2 was assigned a relatively lower rank, thus validating the pipeline's efficacy with the confirmed wet lab experiment that indicate that both RAD51AP1 and XRCC2 were down regulated after treatment in cancer cells. Here, we take one step further by in silico analysis of the 3rd order combinations of RAD51-X-X & RAD51AP1-X-X (X can be known or unknown factor), from a range of 100 randomly picked down regulated genes after ETC-1922159 treatment. The pipeline uses the density based HSIC (Hibert Schmidth Information Criterion) sensitivity index with an rbf (radial basis function) kernel, which is known to be highly effective in sensitivity analysis. Various unknown/unexplored/untested RAD51/RAD51AP1 related 3rd order biological hypotheses emerge some of which are confirmed in wet lab, while others need to be tested.

Subject Areas

WNT pathway; porcupine inhibitor ETC-1922159; sensitivity analysis; colorectal cancer; unknown biological hypotheses; combinatorial search space; support vector ranking; DNA repair and genomic stability factor RAD51

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