(Phospho)proteomic profiling of microsatellite unstable CRC cells reveals alterations in nuclear signaling and cholesterol metabolism caused by frameshift mutation of NMD regulator UPF3A

• Verfasst von: Michalak, Malwina [VerfasserIn]
• Verfasst von: Katzenmaier, Eva-Maria Katharina [VerfasserIn]
• Verfasst von: Röckel, Nina [VerfasserIn]
• Verfasst von: Wörner, Stefan M. [VerfasserIn]
• Verfasst von: Fuchs, Vera [VerfasserIn]
• Verfasst von: Warnken, Uwe [VerfasserIn]
• Verfasst von: Yuan, Yan Ping [VerfasserIn]
• Verfasst von: Bork, Peer [VerfasserIn]
• Verfasst von: Neu-Yilik, Gabriele [VerfasserIn]
• Verfasst von: Kulozik, Andreas [VerfasserIn]
• Verfasst von: Knebel Doeberitz, Magnus von [VerfasserIn]
• Verfasst von: Kloor, Matthias [VerfasserIn]
• Verfasst von: Kopitz, Jürgen [VerfasserIn]
• Verfasst von: Gebert, Johannes [VerfasserIn]
• Titel: (Phospho)proteomic profiling of microsatellite unstable CRC cells reveals alterations in nuclear signaling and cholesterol metabolism caused by frameshift mutation of NMD regulator UPF3A
• Verf.angabe: Malwina Michalak, Eva-Maria Katzenmaier, Nina Roeckel, Stefan M. Woerner, Vera Fuchs, Uwe Warnken, Yan P. Yuan, Peer Bork, Gabriele Neu-Yilik, Andreas Kulozik, Magnus von Knebel Doeberitz, Matthias Kloor, Jürgen Kopitz and Johannes Gebert
• E-Jahr: 2020
• Jahr: 23 July 2020
• Umfang: 21 S.
• Fussnoten: Gesehen am 05.10.2020
• Titel Quelle: Enthalten in: International journal of molecular sciences
• Ort Quelle: Basel : Molecular Diversity Preservation International, 2000
• Jahr Quelle: 2020
• Band/Heft Quelle: 21(2020), 15, Artikel-ID 5234, Seite 1-21
• ISSN Quelle: 1422-0067
• ISSN Quelle: 1661-6596
• DOI: doi:10.3390/ijms21155234
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: coding mononucleotide repeats
• Sach-SW: DNA mismatch repair
• Sach-SW: MSI tumorigenesis
• Sach-SW: nonsense-mediated RNA decay
• Sach-SW: UPF3A
• K10plus-PPN: 1734677856

Abstract

DNA mismatch repair-deficient colorectal cancers (CRCs) accumulate numerous frameshift mutations at repetitive sequences recognized as microsatellite instability (MSI). When coding mononucleotide repeats (cMNRs) are affected, tumors accumulate frameshift mutations and premature termination codons (PTC) potentially leading to truncated proteins. Nonsense-mediated RNA decay (NMD) can degrade PTC-containing transcripts and protect from such faulty proteins. As it also regulates normal transcripts and cellular physiology, we tested whether NMD genes themselves are targets of MSI frameshift mutations. A high frequency of cMNR frameshift mutations in the UPF3A gene was found in MSI CRC cell lines (67.7%), MSI colorectal adenomas (55%) and carcinomas (63%). In normal colonic crypts, UPF3A expression was restricted to single chromogranin A-positive cells. SILAC-based proteomic analysis of KM12 CRC cells revealed UPF3A-dependent down-regulation of several enzymes involved in cholesterol biosynthesis. Furthermore, reconstituted UPF3A expression caused alterations of 85 phosphosites in 52 phosphoproteins. Most of them (38/52, 73%) reside in nuclear phosphoproteins involved in regulation of gene expression and RNA splicing. Since UPF3A mutations can modulate the (phospho)proteomic signature and expression of enzymes involved in cholesterol metabolism in CRC cells, UPF3A may influence other processes than NMD and loss of UPF3A expression might provide a growth advantage to MSI CRC cells.