Passengers are being told only to travel by train if necessary during the latest national strikes by rail workers.
It comes after talks over pay, jobs and terms and conditions failed following the biggest rail strikes in 30 years over three days in June.
Network Rail said only 20% of services will run and some places will have no trains at all on Wednesday.
In a bid to minimise disruption, Network Rail has published a special timetable for Wednesday, with trains set to start later and finish earlier than usual, between 07:00 and 18:30
On Wednesday, the last trains from London will leave for Edinburgh at 14:00, for Birmingham at 15:43 and Manchester at 15:40.
RMT general secretary Mick Lynch said the union would continue to try to reach a deal with Network Rail ahead of Wednesday.
"If we could get a breakthrough then we wouldn't have to take strike action but there's a big gap between the parties at the moment," he told BBC Radio 4's Today programme.
"So I'm not going to raise false hopes but we are constantly in dialogue with all of the elements of the industry."
The Prime Minister's official spokesman said: "We are concerned about the impact this will have on the public going about their everyday lives.
"And we will continue to call on the RMT to call off the strikes, it is in their gift to prevent this disruption."
A strike at Avanti West Coast will disrupt travel to Birmingham the day before the Commonwealth Games begin in the city
All train operators, including Transport for London, will be affected by the strike as Network Rail's signallers control train movements across Great Britain.
The knock-on effects of the disruption are expected to roll in to Thursday, Network Rail said. Further RMT strikes are also planned for 18 and 20 August.
The Transport Salaried Staffs' Association (TSSA) has also announced a strike by its members at Avanti West Coast, which operates some trains to Birmingham, on Wednesday.
It also announced its members will strike on the 18 and 20 of August, affecting Avanti West Coast, c2c, East Midlands Railway, CrossCountry, Great Western Railway, LNER and Southeastern.
On Saturday, there is a separate walkout by train drivers' union Aslef at Arriva Rail London, Greater Anglia, Great Western, Hull Trains, LNER, Southeastern and West Midlands Trains.
Passengers with an advance, off-peak or anytime ticket for 27 or 30 July can travel the day before or up to and including 2 August, Network Rail said.
They can also change their tickets to another date, or get a refund if their train is cancelled or rescheduled.
Those with season tickets for a month or longer who choose not to travel on 27 or 30 July can claim compensation through the delay repay scheme.
Andrew Haines, Network Rail chief executive, said: "Despite our best efforts to find a breakthrough, I'm afraid there will be more disruption for passengers this week as the RMT seems hell-bent on continuing their political campaigning, rather than compromising and agreeing a deal for their members."
The Department for Transport said it was "now clearer than ever" that the RMT has "no interest in engaging in constructive discussions and is hell-bent on creating further misery for passengers across the UK".
"This action is a cynically timed attempt to derail the start of the Commonwealth Games, one of the first major events the country has been able to look forward to since the pandemic," a statement said.
"We continue to encourage RMT to do the right thing by their members and passengers alike and call off the strikes."